1,4-disubstituted pyridazine analogs there of and methods for treating smn-deficiency-related conditions

ABSTRACT

The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof; 
     
       
         
         
             
             
         
       
     
     a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

BACKGROUND OF THE INVENTION

Proximal spinal muscular atrophy (SMA) is an inherited, clinicallyheterogeneous group of neuromuscular disorders characterized bydegeneration of the anterior horn cells of the spinal cord. Patientssuffer from symmetrical weakness of trunk and limb muscles, the legsbeing more affected than the arms and the proximal muscles weaker thanthe distal ones; diaphragm, facial and ocular muscles are spared. Thereare three forms of childhood-onset SMA (types I, II and III), and arelatively recently categorized adult-onset form IV, all of which can bedistinguished on the basis of age of onset and severity of the clinicalcourse assessed by clinical examination, muscle biopsy andelectromyography (EMG)(Munsat T L, Davies K E (1992)).

Type I (Werdnig-Hoffmann disease) is the most acute and severe form,with onset before six months and death usually before two years;children are never able to sit without support. Symptoms of the diseasecan be present in utero, as reduction of fetal movements; at birth; ormore often, within the first four months of life. Affected children areparticularly floppy, experience feeding difficulties and diaphragmaticbreathing, and are characterized by a general weakness in theintercostals and accessory respiratory muscles. Affected children neversit or stand and usually die before the age of 2; death is generally dueto respiratory insufficiency.

Type II (intermediate, chronic form) has onset between six and eighteenmonths of age; muscular fasciculations are common, and tendon reflexesprogressively reduce. Children are unable to stand or walk without aid.Feeding and swallowing problems are not usually present in Type II SMA,although in some patients a feeding tube may become necessary. Mostpatients generally develop a progressive muscular scoliosis which canrequire surgical correction. Like patients with type I disease, clearingof tracheal secretions and coughing might become difficult because ofpoor bulbar function and weak intercostal muscles. These patients haveprofound hypotonia, symmetrical flaccid paralysis, and no control ofhead movement.

Type III (Kugelberg-Welander disease, or Juvenile Spinal MuscularAtrophy) is a mild, chronic form, with onset after the age of 18 months;motor milestones achievement is normal, and deambulation can bepreserved until variable ages. These patients often develop scoliosis,and symptoms of joint overuse, generally caused by weakness, arefrequently seen. Life expectancy is almost normal but quality of life ismarkedly compromised.

Types I, II and III progress over time, accompanied by deterioration ofthe patient's condition.

Adult-onset type IV is characterized by weakness in the second or thirddecade of life, with mild motor impairment not accompanied byrespiratory or nutritional problems. Adult SMA is characterized byinsidious onset and very slow progression. The bulbar muscles are rarelyaffected in Type IV. It is not clear that Type IV SMA is etiologicallyrelated to the Type I-III forms.

Other forms of spinal muscular atrophy include X-linked disease, spinalmuscular atrophy with respiratory distress (SMARD), spinal and bulbarmuscular atrophy (Kennedy's disease, or Bulbo-Spinal Muscular Atrophy),and distal spinal muscular atrophy.

SMA is due to mutations in the Survival of Motor Neuron (SMN) gene,which exists in two forms in humans (SMN1 and SMN2). Loss of SMN isdeleterious to motor neurons and results in neuromuscular insufficiency,a hallmark of the disease. From a genetic point of view, SMA is anautosomal recessive condition, caused by disruption of SMN1 gene,located in 5q13 (Lefebvre S., et al. (1995) Cell 80: 155-165). More than98% of patients with spinal muscular atrophy have a homozygousdisruption of SMN1 by deletion, rearrangement, or mutation. All thesepatients, however, retain at least one copy of SMN2.

At the genomic level, only five nucleotides have been found thatdifferentiate the SMN1 gene from the SMN2 gene. Furthermore, the twogenes produce identical mRNAs, except for a silent nucleotide change inexon 7, i.e., a C→T change six base pairs inside exon 7 in SMN2. Thismutation modulates the activity of an exon splicing enhancer (Lorson andAndrophy (2000) Hum. Mol. Genet. 9:259-265). The result of this and theother nucleotide changes in the intronic and promoter regions is thatmost SMN2 are alternatively spliced, and their transcripts lack exons 3,5, or 7. In contrast, the mRNA transcribed from the SMN1 gene isgenerally a full-length mRNA with only a small fraction of itstranscripts spliced to remove exon 3, 5, or 7 (Gennarelli et al. (1995)Biochem. Biophys. Res. Commun. 213:342-348; Jong et al. (2000) J.Neurol. Sci. 173:147-153). All SMA subjects have at least one, andgenerally two to four copies of the SMN2 gene, which encodes the sameprotein as SMN1; however, the SMN2 gene produces only low levels offull-length SMN protein.

The SMNΔ7 protein is non-functional and thought to be rapidly degraded.About 10% of SMN2 pre-mRNA is properly spliced and subsequentlytranslated into full length SMN protein (FL-SMN), and the rest being theSMNΔ7 copy. The efficiency of SMN2 splicing might be dependent onseverity of disease, and production of a full length transcript of SMN2could range from 10% to 50%. Furthermore, presence or absence of theSMN1 gene, roughly 90% of which becomes the FL-SMN gene product andprotein, influences the severity of SMA by whether or not it cancompensate for the truncated SMNΔ7 copies. A low level of SMN proteinallows embryonic development, but is not sufficient to sustain thesurvival of motor neurons of the spinal cord.

The clinical severity of SMA patients inversely correlates with thenumber of SMN2 genes and with the level of functional SMN proteinproduced (Lorson C L, et al. (1999) PNAS; 96:6307-6311)(Vitali T. et al.(1999) Hum Mol Genet; 8:2525-2532)(Brahe C. (2000) Neuromusc. Disord.;10:274-275)(Feldkotter M, et al. (2002) Am J Hum Genet;70:358-368)(Lefebvre S, et al. (1997) Nature Genet; 16:265-269)(CoovertD D, et al. (1997) Hum Mol Genet; 6:1205-1214)(Patrizi A L, et al.(1999) Eur J Hum Genet; 7:301-309).

Current therapeutic strategies for SMA are mostly centered on elevatingfull length (wild type) SMN protein levels, modulating splicing towardsexon 7 inclusion, stabilizing the wild type protein, and to a lesserextent, on restoring muscle function in SMA by providing trophic supportor by inhibiting skeletal muscle atrophy.

The mechanism leading to motorneuron loss and to muscular atrophy stillremains obscure, although the availability of animal models of thedisease is rapidly increasing knowledge in this field (Frugier T, et al.(2000) Hum Mol. Genet. 9:849-58; Monani U R, et al. (2000) Hum Mol Genet9:333-9; Hsieh-Li H M, et al. (2000) Nat Genet 24:66-70; Jablonka S, etal. (2000) Hum Mol. Genet. 9:341-6). Also the function of SMN protein isstill partially unknown, and studies indicate that it can be involved inmRNA metabolism (Meister G, et al. (2002). Trends Cell Biol. 12:472-8;Pellizzoni L, et al. (2002). Science. 298: 1775-9), and probably intransport of proteins/mRNA to neuromuscular junctions (Ci-fuentes-DiazC, et al. (2002) Hum Mol. Genet. 11: 1439-47; Chan Y B, et al. (2003)Hum Mol. Genet. 12:1367-76; McWhorter M L, et al. (2003) J. Cell Biol.162:919-31; Rossoll W, et al. (2003) J. Cell Biol. 163:801-812).

In addition to the SMAs, a subclass of neurogenic-type arthrogryposismultiplex congenita (congenital AMC) has separately been reported toinvolve SMN1 gene deletion, suggesting that some degree of pathology inthose afflicted is likely due to low levels of motor neuron SMN. (L.Burgien et al., (1996) J. Clin. Invest. 98(5):1130-32. Congenital AMCaffects humans and animals, e.g., horses, cattle, sheep, goats, pigs,dogs, and cats. (M. Longeri et al., (2003) Genet. Sel. Evol.35:S167-S175). Also, the risk of development or the severity ofamyotrophic lateral sclerosis (ALS) has been found to be correlated withlow levels of motor neuron SMN.

There is no cure for SMA available to date and therefore it would beadvantageous to provide novel methods for modulating SMN in order totreat those afflicted with SMA, with neurogenic congenital AMC, ALS, orwith other SMN-deficiency-related conditions. It would further beadvantageous to provide novel drug targets that could be used as a basisfor developing effective therapeutics or diagnostics for such neuronalconditions.

SUMMARY OF THE INVENTION

There remains a need for new treatments and therapies for SpinalMuscular Atrophy. The invention provides compounds, salts thereof,pharmaceutical formulations thereof and combinations thereof whichcompounds are Spinal uscular Atrophy modulators. The invention furtherprovides methods of treating, preventing, or ameliorating SpinalMuscular Atrophy, comprising administering to a subject in need thereofan effective amount of an SMN modulator (e.g., a compound of theinvention).

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

Within certain aspects, SMN modulators provided herein are compounds ofFormula I and salts thereof:

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to the definition of formula (I) or subformulae thereof andone or more pharmaceutically acceptable carriers.

In another embodiment, the invention provides a combination, inparticular a pharmaceutical combination, comprising a therapeuticallyeffective amount of the compound according to the definition of formula(I) or subformulae thereof and one or more therapeutically active.

One embodiment of the invention is to provide a method for treating,preventing, or ameliorating an SMN-deficiency-related condition,comprising administering to a subject in need thereof an effectiveamount of an SMN modulator, or a pharmaceutical composition comprisingthe same.

Another embodiment of the invention is a method of modulating SMNprotein through the administration of an SMN modulator. In anotherembodiment, said SMN modulator is capable of increasing one or more ofFL-SMN or SMNΔ7 levels. In still another embodiment, said SMN modulatoris capable of preventing exon 7 from being spliced from the SMNtranscript.

The present invention is based on the discovery that the SMN modulatorsof the invention (e.g., compounds of formula (I) and/or compounds offormula (I-A) are capable of modulating SMN proteins, e.g., through SMNpromoter activation, splicing modulation (e.g., preventing exon7 frombeing spliced out of the SMN gene), and/or SMN protein stabilitymodulation.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention provides compounds that modulateSMN activity. Such compounds may be used in vitro or in vivo to modulate(preferably increase) SMN production and activity in a variety ofcontexts.

In a first embodiment, the invention provides compounds of Formula I andpharmaceutically acceptable salts thereof, which modulate SMN activity.Compounds of Formula I are represented by the structure:

In a first embodiment, the invention provides compounds, or saltsthereof (preferably pharmaceutically acceptable salts thereof) accordingto Formula (I).

A is 2-hydroxy-phenyl which is substituted with 0, 1, 2, or 3substituents independently selected from C₁-C₄alkyl, wherein 2C₁-C₄alkyl groups can combine with the atoms to which they are bound toform a 5-6 membered ring and is substituted with 0 or 1 substituentsselected from oxo, oxime and hydroxy,haloC₁-C₄alkyl, dihaloC₁-C₄alkyl,trihaloC₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄alkoxy-C₃-C₇cycloalkyl,haloC₁-C₄alkoxy, dihaloC₁-C₄alkoxy, trihaloC₁-C₄alkoxy, hydroxy, cyano,halogen, amino, mono- and di-C₁-C₄alkylamino, heteroaryl, C₁-C₄alkylsubstituted with hydroxy, C₁-C₄alkoxy substituted with aryl, amino,—C(O)NH C₁-C₄alkyl-heteroaryl, —NHC(O)—C₁-C₄alkyl-heteroaryl, C₁-C₄alkylC(O)NH— heteroaryl, C₁-C₄alkyl NHC(O)— heteroaryl, 3-7 memberedcycloalkyl, 5-7 membered cycloalkenyl or 5, 6 or 9 membered heterocyclecontaining 1 or 2 heteroatoms, independently, selected from S, O and N,wherein heteroaryl has 5, 6 or 9 ring atoms, 1, 2 or 3 ring heteroatomsselected from N, O and S and substituted with 0, 1, or 2 substituentsindependently selected from oxo, hydroxy, nitro, halogen, C₁-C₄alkyl,C₁-C₄alkenyl, C₁-C₄alkoxy, C₃-C₇cycloalkyl, C₁-C₄alkyl-OH,trihaloC₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, —C(O)NH₂, —NH₂, —NO₂,hydroxyC1-C₄alkylamino, hydroxyC₁-C₄alkyl, 4-7memberheterocycleC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- anddi-C₁-C₄alkylaminoC₁-C₄alkyl; or A is 2-naphthyl optionally substitutedat the 3 position with hydroxy and additionally substituted with 0, 1,or 2 substituents selected from hydroxy, cyano, halogen, C₁-C₄alkyl,C₂-C₄alkenyl, C₁-C₅alkoxy, wherein the alkoxy is unsubstituted orsubstituted with hydroxy, C₁-C₄alkoxy, amino, N(H)C(O)C₁-C₄alkyl,N(H)C(O)₂ C₁-C₄alkyl, alkylene 4 to 7 member heterocycle, 4 to 7 memberheterocycle and mono- and di-C₁-C₄alkylamino; or A is 6 memberheteroaryl having 1-3 ring nitrogen atoms, which 6 member heteroaryl issubstituted by phenyl or a heteroaryl having 5 or 6 ring atoms, 1 or 2ring heteroatoms independently selected from N, O and S and substitutedwith 0, 1, or 2 substituents independently selected from C₁-C₄alkyl,mono- and di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino, hydroxyC₁-C₄alkyl,aminoC₁-C₄alkyl and mono- and di-C₁-C₄alkylaminoC₁-C₄alkyl; or A isbicyclic heteroaryl having 9 to 10 ring atoms and 1, 2, or 3 ringheteroatoms independently selected from N, O or S, which bicyclicheteroaryl is substituted with 0, 1, or 2 substituents independentlyselected from cyano, halogen, hydroxy, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy and C₁-C₄alkoxy substituted with hydroxy,C₁-C₄alkoxy, amino and mono- and di-C₁-C₄alkylamino; or A is tricyclicheteroaryl having 12 or 13 ring atoms and 1, 2, or 3 ring heteroatomsindependently selected from N, O or S, which tricyclic heteroaryl issubstituted with 0, 1, or 2 substituents independently selected fromcyano, halogen, hydroxy, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₁-C₄alkoxy substituted with hydroxy, C₁-C₄alkoxy, amino,mono- and di-C₁-C₄alkylamino and heteroaryl, wherein said heteroaryl has5, 6 or 9 ring atoms, 1, 2 or 3 ring heteroatoms selected from N, O andS and substituted with 0, 1, or 2 substituents independently selectedfrom oxo, hydroxy, nitro, halogen, C₁-C₄alkyl, C₁-C₄alkenyl,C₁-C₄alkoxy, C₃-C₇cycloalkyl, C₁-C₄alkyl-OH, trihaloC₁-C₄alkyl, mono-and di-C₁-C₄alkylamino, —C(O)NH₂, —NH₂, —NO₂, hydroxyC1-C₄alkylamino,hydroxyC₁-C₄alkyl, 4-7member heterocycleC₁-C₄alkyl, aminoC₁-C₄alkyl andmono- and di-C₁-C₄alkylaminoC₁-C₄alkyl; B is a group of the formula:

wherein m, n and p are independently selected from 0 or 1; R, R₁, R₂,R₃, and R₄ are independently selected from the group consisting ofhydrogen, C₁-C₄alkyl, which alkyl is optionally substituted withhydroxy, amino or mono- and di-C₁-C₄alkylamino; R₅ and R₆ areindependently selected from hydrogen and fluorine; or R and R₃, taken incombination form a fused 5 or 6 member heterocyclic ring having 0 or 1additional ring heteroatoms selected from N, O or S; R₁ and R₃, taken incombination form a C₁-C₃alkylene group; R₁ and R₅, taken in combinationform a C₁-C₃alkylene group; R₃ and R₄, taken in combination with thecarbon atom to which they attach, form a spirocyclicC₃-C₆cycloalkyl; Xis CR_(A)R_(B), O, NR₇ or a bond; R₇ is hydrogen, or C₁-C₄alkyl; R_(A)and R_(B) are independently selected from hydrogen and C₁-C₄alkyl, orR_(A) and R_(B), taken in combination, form a divalent C₂-C₅alkylenegroup; Z is CR₈ or N; when Z is N, X is a bond; R₈ is hydrogen or takenin combination with R₆ form a double bond; or B is a group of theformula:

wherein p and q are independently selected from the group consisting of0, 1, and 2; R₉ and R₁₃ are independently selected from hydrogen andC₁-C₄alkyl; R₁₀ and R₁₄ are independently selected from hydrogen, amino,mono- and di-C₁-C₄alkylamino and C₁-C₄alkyl, which alkyl is optionallysubstituted with hydroxy, amino or mono- and di-C₁-C₄alkylamino; R₁₁ ishydrogen, C₁-C₄alkyl, amino or mono- and di-C₁-C₄alkylamino; R₁₂ ishydrogen or C₁-C₄alkyl; or R₉ and R₁₁, taken in combination form asaturated azacycle having 4 to 7 ring atoms which is optionallysubstituted with 1-3 C₁-C₄alkyl groups; or R₁₁ and R₁₂, taken incombination form a saturated azacycle having 4 to 7 ring atoms which isoptionally substituted with 1-3 C₁-C₄alkyl groups.

In a second embodiment, the invention is a compound according to thefirst embodiment, or a salt thereof, wherein A is 6 member heteroarylhaving 1-3 ring nitrogen atoms, which 6 member heteroaryl is substitutedby phenyl or a heteroaryl having 5 or 6 ring atoms, 1 or 2 ringheteroatoms independently selected from N, O and S and substituted with0, 1, or 2 substituents independently selected from C₁-C₄alkyl, mono-and di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino, hydroxyC₁-C₄alkyl,aminoC₁-C₄alkyl and mono- and di-C₁-C₄alkylaminoC₁-C₄alkyl; or A isbicyclic heteroaryl having 9 to 10 ring atoms and 1, 2, or 3 ringheteroatoms independently selected from N, O or S, which heteroaryl issubstituted with 0, 1, or 2 substituents independently selected fromcyano, halogen, hydroxy, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy and C₁-C₄alkoxy substituted with hydroxy, C₁-C₄alkoxy, aminoand mono- and di-C₁-C₄alkylamino.

In a third embodiment, the invention is a compound according to thefirst embodiment, or a salt thereof, wherein A is 2-hydroxy-phenyl whichis substituted with 0, 1, 2, or 3 substituents independently selectedfrom C₁-C₄alkyl, haloC₁-C₄alkyl C₁-C₄alkoxy, hydroxy, cyano, halogen,amino, mono- and di-C₁-C₄alkylamino, heteroaryl and C₁-C₄alkylsubstituted with hydroxy or amino, which heteroaryl has 5 or 6 ringatoms, 1 or 2 ring heteroatoms selected from N, O and S and substitutedwith 0, 1, or 2 substituents independently selected from C₁-C₄alkyl,mono- and di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino, hydroxyC₁-C₄alkyl,4-7member heterocycleC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- anddi-C₁-C₄alkylaminoC₁-C₄alkyl.

In a fourth embodiment, the invention is a compound according to thefirst embodiment, or a salt thereof, wherein A is 2-naphthyl optionallysubstituted at the 3 position with hydroxy and additionally substitutedwith 0, 1, or 2 substituents selected from hydroxy, cyano, halogen,C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkoxy, wherein the alkoxy isunsubstituted or substituted with hydroxy, C₁-C₄alkoxy, amino,N(H)C(O)C₁-C₄alkyl, N(H)C(O)₂ C₁-C₄alkyl, 4 to 7 member heterocycle andmono- and di-C₁-C₄alkylamino; or

In a fifth embodiment, the invention is a compound according to thefirst through fourth embodiments, or a salt thereof, wherein B is agroup of the formula:

wherein m, n and p are independently selected from 0 or 1; R, R₁, R₂,R₃, and R₄ are independently selected from the group consisting ofhydrogen, C₁-C₄alkyl, which alkyl is optionally substituted withhydroxy, amino or mono- and di-C₁-C₄alkylamino; R₅ and R₆ are hydrogen;or R and R₃, taken in combination form a fused 5 or 6 memberheterocyclic ring having 0 or 1 additional ring heteroatoms selectedfrom N, O or S; R₁ and R₃, taken in combination form a C₁-C₃alkylenegroup; R₁ and R₅, taken in combination form a C₁-C₃alkylene group; R₃and R₄, taken in combination with the carbon atom to which they attach,form a spirocyclicC₃-C₆cycloalkyl; X is CR_(A)R_(B), O, NR₇ or a bond;R_(A) and R_(B) are independently selected from hydrogen and C₁-C₄alkyl,or R_(A) and R_(B), taken in combination, form a divalent C₂-C₅alkylenegroup; Z is CR₈ or N; when Z is N, X is a bond; R₈ is hydrogen or takenin combination with R₆ form a double bond.

In a sixth embodiment, the invention is a compound according to thefirst through fourth embodiments, or a salt thereof, wherein B is agroup of the formula:

wherein p and q are independently selected from the group consisting of0, 1, and 2; R₉ and R₁₃ are independently selected from hydrogen andC₁-C₄alkyl; R₁₀ and R₁₄ are independently selected from hydrogen, amino,mono- and di-C₁-C₄alkylamino and C₁-C₄alkyl, which alkyl is optionallysubstituted with hydroxy, amino or mono- and di-C₁-C₄alkylamino; R₁₁ ishydrogen, C₁-C₄alkyl, amino or mono- and di-C₁-C₄alkylamino; R₁₂ ishydrogen or C₁-C₄alkyl; or R₉ and R₁₁, taken in combination form asaturated azacycle having 4 to 7 ring atoms which is optionallysubstituted with 1-3 C₁-C₄alkyl groups; or R₁₁ and R₁₂, taken incombination form a saturated azacycle having 4 to 7 ring atoms which isoptionally substituted with 1-3 C₁-C₄alkyl groups.

In a seventh embodiment, the invention the invention is a compoundaccording to the first or third embodiments, or a salt thereof, whichcompound is represented by Formula (II):

wherein R₁₅ is hydrogen, hydroxyl, C₁-C₄alkoxy, which alkoxy isoptionally substituted with hydroxy, methoxy, amino, mono- anddi-methylamino or morpholine.

In an eighth embodiment, the invention is a compound of the first orfourth embodiments, or a salt thereof, which compound is represented byFormula (III):

wherein R₁₆ is a 5 member heteroaryl having one ring nitrogen atom and 0or 1 additional ring heteroatom selected from N, O or S, wherein theheteroaryl is optionally substituted with C₁-C₄alkyl.

In a ninth embodiment, the invention is a compound of the first throughfourth, seventh and eighth embodiments, or salt thereof, wherein B isselected from the group consisting of

wherein X is O or N(Me); and R₁₇ is hydrogen or methyl.

In a tenth embodiment, the invention is a compound according to thefirst through fifth and seventh through ninth embodiments, or saltthereof, wherein X is —O—.

In an eleventh embodiment, the invention is a compound according to thefirst through fifth and seventh through ninth embodiments, or saltthereof, wherein B is:

In a twelfth embodiment, the invention is a compound of the eighththrough eleventh embodiments, or salt thereof, wherein R₁₆ is:

In a thirteenth embodiment, the invention is a compound of the firstembodiment, or salt thereof, wherein the compound is of formula (IV):

wherein X is —O— or

R′ is a 5-membered heteroaryl optionally substituted with 0, 1, or 2groups selected from oxo, hydroxy, nitro, halogen, C₁-C₄alkyl,C₁-C₄alkenyl, C₁-C₄alkoxy, C₃-C₇cycloalkyl, C₁-C₄alkyl-OH,trihaloC₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, —C(O)NH₂, —NH₂, —NO₂,hydroxyC1-C₄alkylamino, hydroxyC₁-C₄alkyl, 4-7memberheterocycleC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- anddi-C₁-C₄alkylaminoC₁-C₄alkyl.

In a fourteenth embodiment, the invention is a compound, or saltthereof, selected from the group consisting of:

-   6-(naphthalen-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;-   6-(benzo[b]thio-phen-2-yl)-N-methyl-N-(2,2,6,6-tetra-methylpiperidin-4-yl)pyridazin-3-amine;-   2-(6-(2,2,6,6-tetramethylpiperidin-4-ylamino)-pyridazin-3-yl)phenol;-   2-(6-(methyl-(2,2,6,6-tetra-methylpiperidin-4-yl)amino)pyridazin-3-yl)benzo[b]-thiophene-5-carbonitrile;-   6-(quinolin-3-yl)-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine;-   3-(benzo[b]-thiophen-2-yl)-6-(2,2,6,6-tetra-methylpiperidin-4-yloxy)pyridazine;-   2-(6-(methyl-(2,2,6,6-tetra-methylpiperidin-4-yl)amino)-pyridazin-3-yl)phenol;-   6-(6-(methyl-(2,2,6,6-tetra-methylpiperidin-4-yl)amino)-pyridazin-3-yl)naphthalen-2-ol;-   6-(benzo[b]-thiophen-2-yl)-N-(2,2,6,6-tetra-methylpiperidin-4-yl)pyridazin-3-amine;-   7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline;-   6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline;-   N-methyl-6-(quinolin-7-yl)-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine;-   N-methyl-6-(quinolin-6-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;-   6-(isoquinolin-7-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;-   6-(isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;-   6-(imidazo[1,2-a]pyridin-6-yl-pyridazin-3-yl)-methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine;-   methyl-[6-(6-phenyl-pyridin-3-yl)-pyridazin-3-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine;-   methyl-[6-(6-pyrrol-1-yl-pyridin-3-yl)-pyridazin-3-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine;-   methyl-[6-(6-pyrazol-1-yl-pyridin-3-yl)-pyridazin-3-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine;-   methyl-(6-quinoxalin-2-yl-pyridazin-3-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine;-   methyl-(6-quinolin-3-yl-pyridazin-3-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine;-   N-methyl-6-(phthalazin-6-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;-   6-(benzo[c][1,2,5]oxa-diazol-5-yl)-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine;-   6-(benzo[d]thiazol-5-yl)-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine;-   6-(2-methylbenzo-[d]oxazol-6-yl)-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine;-   3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;-   5-chloro-2-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   3-(6-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyridazin-3-yl)naphthalen-2-ol;-   5-chloro-2-(6-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyridazin-3-yl)phenol;-   4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile;-   3-[6-(2,2,6,6-tetramethyl-piperidin-4-yloxy)-pyridazin-3-yl]-naphthalen-2-ol;-   2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-4-trifluoromethyl-phenol;-   2-fluoro-6-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;-   3,5-dimethoxy-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;-   4,5-dimethoxy-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;-   5-methoxy-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]pyridazin-3-yl}-phenol;-   4,5-difluoro-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;-   5-fluoro-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;-   3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile;-   1-allyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;-   6-(benzo[b]thiophen-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine;-   N-allyl-3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzamide;-   2-(6-(methyl    (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   5-(5-methyl-oxazol-2-yl)-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]pyridazin-3-yl}-phenol;-   5-(4-hydroxymethyl)-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(1H-imidazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethyl-piperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(4-amino-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(4-amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(3-amino-pyrazol-1-yl)-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]pyridazin-3-yl}-phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-(2-morpholino-ethyl)-1H-pyrazol-4-yl)phenol;-   2-(6-(methyl    (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   5-(5-amino-1H-pyrazol-1-yl)-2-(6-(methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)amino)pyridazin-3-yl)phenol;-   2-(6-(methyl    (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-1-yl)phenol;-   2-{6-[(2-hydroxy-ethyl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]pyridazin-3-yl}-5-pyrazol-1-yl-phenol;-   2-(6-(piperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   2-(6-(((2S,4R,6R)-2,6-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   2-(6-((-2,6-di methyl    piperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   2-(6-((-2,6-di methyl    piperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-yloxy)pyridazin-3-yl)phenol;-   2-(6-((-2-methylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   (S)-5-(1H-Pyrazol-1-yl)-2-(6-(pyrrolidin-3-ylmethoxy)pyridazin-3-yl)phenol;-   (R)-5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-ylmethoxy)pyridazin-3-yl)phenol;-   2-(6-((3-fluoropiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)-phenol;-   2-[6-(1,2,2,6,6-pentamethyl-piperidin-4-yloxy)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   5-pyrazol-1-yl-2-[6-(2,2,6,6-tetramethyl-piperidin-4-yloxy)-pyridazin-3-yl]-phenol;-   5-(1H-Pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol.;-   2-(6-piperazin-1-yl-pyridazin-3-yl)-5-pyrazol-1-yl-phenol;-   3-[6-(azetidin-3-ylamino)-pyridazin-3-yl]-naphthalen-2-ol;-   2-[6-(azetidin-3-ylamino)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   2-[6-(3,5-di    methyl-piperazin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   2-[6-(7-methyl-2,7-diaza-spiro[4.4]non-2-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   2-(6-[1,4]diazepan-1-yl-pyridazin-3-yl)-5-pyrazol-1-yl-phenol;-   2-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridazin-3-yl}-5-pyrazol-1-yl-phenol;-   2-[6-(3,6-diaza-bicyclo[3.2.1]oct-3-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   2-[6-(2,7-diaza-spiro[3.5]non-7-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   2-[6-(3-hydroxy-methyl-piperazin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   2-[6-(1,7-diaza-spiro[4.4]non-7-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   2-[6-(4-amino-4-methyl-piperidin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   2-[6-(3-dimethyl-amino-piperidin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   2-[6-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   2-[6-(3,3-di    methyl-piperazin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;-   2-(6-(7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]-nonan-2-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   3-(6-(piperazin-1-yl)pyridazin-3-yl)naphthalene-2,7-diol;-   5-pyrazol-1-yl-2-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-phenol;-   2-(6-piperidin-4-yl-pyridazin-3-yl)-5-pyrazol-1-yl-phenol;-   3-(6-(1,2,3,6-tetra-hydropyridin-4-yl)pyridazin-3-yl)naphthalen-2-ol;-   3-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol;-   3-(6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol;-   3-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol;-   3-(6-(piperidin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol;-   3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalene-2,7-diol;-   3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol;-   3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol;-   [3-(7-hydroxy-6-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-yloxy)-propyl]-carbamic    acid tert-butyl ester;-   7-(3-amino-propoxy)-3-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-ol;-   N-[3-(7-hydroxy-6-{6[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-yloxy)-propyl]-acetamide;-   7-(3-hydroxypropoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;-   7-(3-methoxypropoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;-   7-(2-morpholinoethoxy)-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalen-2-ol;-   3-(6-(piperidin-4-ylmethyl)pyridazin-3-yl)naphthalen-2-ol;-   5-(1H-pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol;-   3-methoxy-2-(6-(methyl    (2,2,6-trimethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol;-   2-(6-((6S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2-naphthonitrile;-   3-(6-(methyl    (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(piperidin-1-ylmethyl)naphthalen-2-ol;-   3-(6-(methyl    (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(pyrrolidin-1-ylmethyl)naphthalen-2-ol;-   1-bromo-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol;-   1-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol;-   7-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;-   7-methoxy-3-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;-   7-(3,6-dihydro-2H-pyran-4-yl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;-   3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)naphthalen-2-ol;-   7-(difluoromethyl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;-   7-((4-hydroxy-2-methylbutan-2-yl)oxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;-   7-(3-hydroxy-3-methylbutoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)benzene-1,3-diol;-   3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenol;-   4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyl)-1-methylpyridin-2(1H)-one;-   3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)phenol;-   3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(pyridin-3-yl)phenol;-   5-(1-cyclopentyl-1H-pyrazol-4-yl)-3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   3′,5-dimethoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-[1,1′-biphenyl]-3-ol;-   3-(benzyloxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol;-   3-ethoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol;-   3-(cyclopropylmethoxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol;-   2-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1H-benzo[d]imidazol-6-ol;-   5-chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(1H-pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile;-   2-(6-((2,2-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-4-yl)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenol;-   4-(1H-indol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   4-(cyclopent-1-en-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-3-yl)phenol;-   4-(4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-2-ol;-   4-(4-hydroxy-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one;-   4-(4-hydroxy-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)pyridin-2-ol;-   5-(1H-indazol-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   4-chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   4-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   5-fluoro-4-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-4-yl)phenol;-   5-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-5-yl)phenol;-   6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one;-   6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1,4-dihydroindeno[1,2-c]pyrazol-7-ol;-   6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one    oxime hydrochloride salt;-   5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-indene-1,6-diol;-   2-amino-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-8H-indeno[1,2-d]thiazol-5-ol    hydrochloride salt;-   9-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5,6-dihydroimidazo[5,1-a]isoquinolin-8-ol    hydrochloride salt;-   4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide;-   4-(4-(hydroxymethyl)-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol;-   6-(3-(benzyloxy)isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;-   6-(1-(benzyloxy)isoquinolin-7-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;-   3-fluoro-5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol    hydrochloride salt;-   4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-2(1H)-one    hydrochloride salt;-   4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one    hydrochloride salt;-   5-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one    hydrochloride salt;-   3-fluoro-5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol    hydrochloride salt;-   5-chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol    hydrochloride salt;-   3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol    hydrochloride salt;-   3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol    hydrochloride salt;-   5-(5-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(3-hydroxy-4-(6-methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-2-ol;-   4-(3-hydroxy-4-(6-methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-2-ol;-   5-(6-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-3-(trifluoromethyl)pyridin-2-ol;-   5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one;-   4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one;-   5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   4-(3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)pyridin-2-ol;-   5-(6-(dimethylamino)pyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   4-(3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(pyrimidin-5-yl)phenol;-   5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-3-ol;-   1-cyclopropyl-4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-2(1H)-one;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)phenol;-   5-(cyclopent-1-en-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(3,6-dihydro-2H-pyran-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(imidazo[1,5-a]pyridin-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(imidazo[1,2-a]pyridin-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(2-methylpyridin-4-yl)phenol;-   5-(1H-imidazol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   5-(imidazo[1,2-a]pyrazin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(4-methyl-1H-imidazol-2-yl)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-imidazol-4-yl)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-imidazol-5-yl)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(4-nitro-1H-imidazol-2-yl)phenol;-   2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(2-methyl-1H-imidazol-4-yl)phenol;-   5-(1,2-dimethyl-1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;-   1-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1H-pyrazole-4-carboxamide;-   2-(6-((3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(6-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;-   4-(3-hydroxy-4-(6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one;-   4-(3-hydroxy-4-(6-((3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one;-   2-(6-(2,7-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;    and-   4-(4-(6-(2,7-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one.

In a fifteenth embodiment, the invention is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound according toany one of the firsth through fourteenth embodiments, or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers.

In a sixteenth embodiment, the invention is a combination comprising atherapeutically effective amount of a compound according to any one ofthe first through fourteenth embodiments or a pharmaceuticallyacceptable salt thereof and one or more therapeutically activeco-agents.

In a seventeenth embodiment, the invention is a method to treat, preventor ameliorate an SMN-deficiency-related condition, comprisingadministering to a subject in need thereof an effective amount of acompound or salt thereof of any one of the first through fourteenthembodiments.

In an eighteenth embodiment, the invention is the method of theseventeenth embodiment, wherein said SMN-deficiency-related condition isSpinal Muscular Atrophy.

In a nineteenth embodiment, the invention is a compound according to anyone of the first through fourteenth embodiments or a pharmaceuticallyacceptable salt thereof, for use as a medicament.

In a twentieth embodiment, the invention is a compound according to anyone of the first through fourteenth embodiments or a pharmaceuticallyacceptable salt thereof, for use in the treatment of anSMN-deficiency-related condition.

In a twentyfirst embodiment, the invention is the compound according tothe twentieth embodiment, or pharmaceutically acceptable salt thereof,for use in the treatment of spinal muscular atrophy.

In a twentysecond embodiment, the invention is use of a compoundaccording to any one of the first through fourteenth embodiments, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of spinal muscular atrophy.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “SMN modulator” includes agents, such as thecompounds of the invention, which possess the ability to modulate, e.g.,increase, SMN protein levels by at least one of multiple possiblemechanisms. A non-limiting set of mechanisms includes SMN promoteractivation, splicing modulation (e.g., preventing exon7 from beingspliced out of the SMN gene), and SMN protein stability modulation. SMNmodulators can modulate, e.g., increase FL-SMN and/or SMNΔ7 levels viaany of said mechanisms, and/or can prevent SMNΔ7 from being degraded.

As used herein, the term “compounds of the invention” include but arenot limited to the compounds of formula (I) and the compounds of formula(I-A)

As used herein, the term “SMN-deficiency-related conditions” includesbut is not limited to Spinal Muscular Atrophy (SMA), neurogenic-typearthrogryposis multiplex congenita (congenital AMC), and amyotrophiclateral sclerosis (ALS).

As used herein, the term “Spinal Muscular Atrophy”, “SMA,” include threeforms of childhood-onset SMA: Type I (Werdnig-Hoffmann disease); Type II(intermediate, chronic form), Type III (Kugelberg-Welander disease, orJuvenile Spinal Muscular Atrophy); Adult-onset type IV; as well as otherforms of SMA, including X-linked disease, spinal muscular atrophy withrespiratory distress (SMARD), spinal and bulbar muscular atrophy(Kennedy's disease, or Bulbo-Spinal Muscular Atrophy), and distal spinalmuscular atrophy.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “C₁₋₁₀alkyl” refers to a fully saturatedbranched or unbranched hydrocarbon moiety having 1 to 10 carbon atoms.The terms “C₁₋₆alkyl” and “C₁₋₄alkyl” are to be construed accordingly.Representative examples of C₁₋₁₀alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl andn-decyl.

As used herein, the term “C₁₋₁₀alkylene” refers to divalent alkyl groupas defined herein above having 1 to 10 carbon atoms. The terms“C₁₋₆alkylene” and “C₁₋₄alkylene” are to be construed accordingly.Representative examples of C₁₋₁₀alkylene include, but are not limitedto, methylene, ethylene, n-propylene, iso-propylene, n-butylene,sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene,neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene,2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene andn-decylene.

As used herein, the term “haloC₁₋₁₀alkyl” refers to a C₁₋₁₀alkyl groupas defined herein, wherein at least one of the hydrogen atoms isreplaced by a halo atom. The haloC₁₋₁₀alkyl group can bemonohaloC₁₋₁₀alkyl, dihaloC₁₋₁₀alkyl or polyhaloC₁₋₁₀alkyl includingperhaloC₁₋₁₀alkyl. A monohaloC₁₋₁₀alkyl can have one iodo, bromo, chloroor fluoro within the alkyl group. DihaloC₁₋₁₀alkyl andpolyhaloC₁₋₁₀alkyl groups can have two or more of the same halo atoms ora combination of different halo groups within the alkyl. Typically thepolyhaloC₁₋₁₀alkyl group contains up to 12, or 10, or 8, or 6, or 4, or3, or 2 halo groups. Non-limiting examples of haloC₁₋₁₀alkyl includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. A perhaloC₁₋₁₀alkylgroup refers to an C₁₋₁₀alkyl group having all hydrogen atoms replacedwith halo atoms.

The term “aryl” refers to an aromatic hydrocarbon group having 6-20carbon atoms in the ring portion. Typically, aryl is monocyclic,bicyclic or tricyclic aryl having 6-20 carbon atoms and includes one ormore aromatic rings fused to one or more non-aromatic hydrocarbon rings.Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.

As used herein, the term “C₁₋₁₀alkoxy” refers to C₁₋₁₀alkyl-O—, whereinC₁₋₁₀alkyl is defined herein above. Representative examples ofC₁₋₁₀alkoxy include, but are not limited to, methoxy, ethoxy, propoxy,2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy,octyloxy- and decyloxy-.

As used herein, the term “heterocyclyl” or “heterocyclo” refers to asaturated or unsaturated non-aromatic ring or ring system, which is a4-, 5-, 6-, or 7-membered monocyclic ring containing 1, 2 or 3heteroatoms selected from O, S and N, a 7-, 8-, 9-, 10-, 11-, or12-membered bicyclic ring system containing 1, 2, 3, 4 or 5 heteroatomsselected from O, S and N, or a 10-, 11-, 12-, 13-, 14- or 15-memberedtricyclic ring system and containing 1, 2, 3, 4, 5, 6 or 7 heteroatomsselected from O, S and N, where the N and S can also optionally beoxidized to various oxidation states. The heterocyclic group can beattached via a heteroatom or a carbon atom. The heterocyclyl can includefused or bridged rings as well as spirocyclic rings. Examples ofheterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane,morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane,imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran,dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane,oxathiane and thiomorpholine.

As used herein, the term “C₃₋₁₂cycloalkyl” refers to saturated orunsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12carbon atoms. The term “C₃₋₁₈cycloalkyl” refers to a fully saturated orunsaturated monocyclic hydrocarbon group of 3-8 carbon atoms. Exemplarymonocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl. Exemplary bicyclic hydrocarbon groups include bornyl,indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl. Exemplary tricyclic hydrocarbon groups include, forexample, adamantyl.

As used herein the term “C₃₋₁₂cycloalklyoxy” refers toC₃₋₁₂cycloalkyl-O—, wherein C₃₋₁₂cycloalkyl is defined herein above.Representative examples of C₃₋₁₂cycloalklyoxy include, but are notlimited to monocyclic groups such as cyclopropoxy, cyclobutoxy,cyclopentyloxy, cyclopentenyloxy, cyclohexyloxy and cyclohexenyloxy andthe like. Exemplary bicyclic hydrocarbon groups include bornyloxy,indyloxy, hexahydroindyloxy, tetrahydronaphthyloxy,decahydronaphthyloxy, bicyclo[2.1.1]hexyloxy, bicyclo[2.2.1]heptyloxy,bicyclo[2.2.1]heptenyloxy, 6,6-dimethylbicyclo[3.1.1]heptyloxy,2,6,6-trimethylbicyclo[3.1.1]heptyloxy, bicyclo[2.2.2]octyloxy and thelike. Exemplary tricyclic hydrocarbon groups include, for example,adamantyloxy.

As used herein, the term “aryloxy” refers to both an —O-aryl and an—O-heteroaryl group, wherein aryl and heteroaryl are defined herein.

As used herein, the term “heteroaryl” refers to a 5-, 6-, or 7-memberedmonocyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms selectedfrom O, S and N, an 8-, 9-, or 10-membered fused bicyclic ring systemcontaining 1, 2, 3, 4 or 5 heteroatoms selected from O, S and N, or an11-, 12-, 13-, or 14-membered fused tricyclic ring system containing 1,2, 3, 4, 5 or 6 heteroatoms selected from O, S and N, wherein at leastone of the rings of the bicyclic or tricyclic ring systems is fullyaromatic. Typical heteroaryl groups include 2- or 3-thienyl, 2- or3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-,or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or5-pyrimidinyl, 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-,6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-,6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-,6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7-, or8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-,or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4-aH carbazolyl, 1-, 2-,3-, 4-, 5-, 6-, 7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-,2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-,or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-,2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-,or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or I-, 3-, 4-, 5-, 6-, 7-, 8-, 9-,or 10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-,6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl,2-, 3-, 5-, 6-,or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl,2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl,1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-,8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-,or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-,4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-,or 11-1H-pyrrolo[1,2-b][2]benzazapinyl, 2-, 3-, 4-, 5-, 6-, 7-, or8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-,5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-,5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-,4-, 5-, 6-, or 7-benzothiazolyl.

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo, and iodo.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R—S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers or axes and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts.” The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulformate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound, a basic or acidic moiety, byconventional chemical methods. Generally, such salts can be prepared byreacting free acid forms of these compounds with a stoichiometric amountof the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, use of non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile isdesirable, where practicable. Lists of additional suitable salts can befound, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H, ¹³C, and ¹⁴C, are present. Such isotopicallylabelled compounds are useful in metabolic studies (with ¹⁴C), reactionkinetic studies (with, for example ²H or ³H), detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviate, inhibit,prevent and/or ameliorate a condition, or a disorder or a disease (i)mediated by Survival of Motor Neuron (SMN) gene or gene product, or bySMNΔ7 degradation, or by the relative levels of FL-SMN and SMNΔ7 (ii)associated with SMN activity, or (iii) characterized by activity (normalor abnormal) of SMN; or (2) reducing or inhibiting the activity of SMN;or (3) reducing or inhibiting the expression of SMN1 or SMN2.

In another non-limiting embodiment, the term “a therapeuticallyeffective amount” refers to the amount of the compound of the presentinvention that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to at leastpartially reducing or inhibiting the activity of SMN; or at leastpartially reducing or inhibiting the expression of SMN, in both cases bymodulating the relative levels of FL-SMN and SMNΔ7.

The phrases “therapeutically effective amount” and “effective amount”are used herein to mean an amount sufficient to reduce by at least about15 percent, preferably by at least 50 percent, more preferably by atleast 90 percent, and most preferably prevent, a clinically significantdeficit in the activity, function and response of the host.Alternatively, a therapeutically effective amount is sufficient to causean improvement in a clinically significant condition/symptom in thehost.

The effective amount can vary depending on such factors as the size andweight of the subject, the type of illness, or the particular compoundof the invention. For example, the choice of the compound of theinvention can affect what constitutes an “effective amount.” One ofordinary skill in the art would be able to study the factors containedherein and make the determination regarding the effective amount of thecompounds of the invention without undue experimentation.

The regimen of administration can affect what constitutes an effectiveamount. The compound of the invention can be administered to the subjecteither prior to or after the onset of an SMN-deficiency-relatedcondition. Further, several divided dosages, as well as staggereddosages, can be administered daily or sequentially, or the dose can becontinuously infused, or can be a bolus injection. Further, the dosagesof the compound(s) of the invention can be proportionally increased ordecreased as indicated by the exigencies of the therapeutic orprophylactic situation.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat,” “treating,” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically (e.g., throughstabilization of a discernible symptom), physiologically, (e.g., throughstabilization of a physical parameter), or both. In yet anotherembodiment, “treat,” “treating,” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Compounds of the present invention are either obtained in the free form,as a salt thereof, or as prodrug derivatives thereof.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention may also form internalsalts, e.g., zwitterionic molecules.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure material.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known to those skilled in theart.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. The pharmaceutical composition can be formulated forparticular routes of administration such as oral administration,parenteral administration, and rectal administration, etc. In addition,the pharmaceutical compositions of the present invention can be made upin a solid form (including without limitation capsules, tablets, pills,granules, powders or suppositories), or in a liquid form (includingwithout limitation solutions, suspensions or emulsions). Thepharmaceutical compositions can be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents, or buffering agents, aswell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with

diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;

lubricants, e.g., silica, talcum, stearic acid, its magnesium or calciumsalt and/or polyethyleneglycol; for tablets also

binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired

disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or

absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The compounds of formula I in free form or in salt form, exhibitvaluable pharmacological properties, e.g. full length SMN proteinproduction modulating properties, e.g. as indicated in in vitro and invivo tests as provided in the next sections, and are therefore indicatedfor therapy or for use as research chemicals, e.g. as tool compounds.

Thus, as a further embodiment, the present invention provides the use ofa compound of formula (I) or a salt thereof in therapy. In a furtherembodiment, the therapy is selected from a disease which may be treatedby modulating full length SMN protein production. In another embodiment,the disease is selected from the afore-mentioned list, suitably spinalmuscular atrophy.

In another embodiment, the invention provides a method of treating adisease which is treated by modulating full length SMN proteinproduction comprising administration of a therapeutically acceptableamount of a compound of formula (I) or salt thereof to a patient in needof such therapy. In a further embodiment, the disease is selected fromthe afore-mentioned list, suitably spinal muscular atrophy.

Thus, as a further embodiment, the present invention provides the use ofa compound of formula (I) or salt thereof for the manufacture of amedicament. In a further embodiment, the medicament is for treatment ofa disease which may be treated by modulation of SMN protein production.In another embodiment, the disease is selected from the afore-mentionedlist, suitably spinal muscular atrophy.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 0.01-1000 mg of active ingredient(s) fora subject of about 0.05-70 kg or about 1-20 kg, or about 1-500 mg orabout 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 0.01-1 mgor about 0.01-0.1 mg or about 1-50 mg of active ingredients. Thetherapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a spinalmuscular atrophy. Products provided as a combined preparation include acomposition comprising the compound of formula (I) and the othertherapeutic agent(s) together in the same pharmaceutical composition, orthe compound of formula (I) and the other therapeutic agent(s) inseparate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Celsius. If not mentioned otherwise, all evaporations areperformed under reduced pressure, typically between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

Preparations of Compounds

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocesses described below the functional groups of intermediatecompounds may need to be protected by suitable protecting groups. Suchfunctional groups include hydroxy, phenol, amino and carboxylic acid.Suitable protecting groups for hydroxy or phenol include trialkylsilylor diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl,and the like. Suitable protecting groups for amino, amidino andguanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.Suitable protecting groups for carboxylic acid include alkyl, aryl orarylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein. The use of protecting groups is described in detail inGreen, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis(1999), 3rd Ed., Wiley. The protecting group may also be a polymerresin, such as a Wang resin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a subjectand thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

The following reaction schemes illustrate methods to make compounds ofthis invention. It is understood that one skilled in the art would beable to make these compounds by similar methods or by methods known toone skilled in the art. In general, starting components and reagents maybe obtained from sources such as Sigma Aldrich, Lancaster Synthesis,Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, Strem,other commercial vendors, or synthesized according to sources known tothose skilled in the art, or prepared as described in this invention. A,B, X, R, R¹, R², R³, R⁴, are defined as in the Specification unlessspecifically defined.

In general, pyridazine compounds of Formula (I) of this invention can besynthesized following the general procedure described in Scheme 1.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe invention are prepared in the above reaction Scheme 1 as follows:

Di-halopyridazine (1) reacts in a displacement reaction or ametal-mediated cross coupling reaction (Buchwald) with an alcohol or anamine (B) to provide pyridazine intermediate (2). Transitionmetal-mediated cross coupling reaction, such as a Suzuki reaction,between halide compound (2) and a substituted aryl or heteroarylcompound A, such as a boronate acid or boronate ester, provides compound(3) of Formula (I) of the invention.

In a complementary manner, compounds of Formula (I) can be synthesizedfollowing the general procedure described in Scheme 2.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe invention are prepared in the above reaction Scheme 2 as follows:

Di-halopyridazine (1) reacts in a transition metal-mediated crosscoupling reaction, such as a Suzuki reaction, with a substituted aryl orheteroaryl compound A, such as a boronate acid or ester, to providepyridazine intermediate (4). Pyridazine intermediate (4) reacts via adisplacement reaction with an alcohol or an amine (B) to providepyridazine (3) of Formula (I) of the invention.

Compounds of Formula (I) can also be prepared following the generalprocedure described in Scheme 3.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe invention are prepared in the above reaction Scheme 3 as follows:

Di-halopyridazine (1) reacts in a transition metal-mediated crosscoupling reaction, such as a Suzuki reaction, with a substituted aryl orheteroaryl compound A, such as a boronate acid or ester, to providepyridazine intermediate (4). Pyridazine intermediate (4) reacts viasecond metal-mediated cross coupling, such as a Suzuki reaction, toprovide pyridazine (3) of Formula (I) of the invention.

General Schemes 1, 2 and 3 can be followed for a variety of aromatic Agroups such as substituted phenols, naphthyls, heteroaryls, and thelike, and for a variety of amine or alcohol B groups such as substitutedaminopiperidines, piperazines, homopiperazines, 4-hydroxy piperidines,and the like, to provide compounds of Formula (I) of the invention.Routine protecting group strategies may be required to achieve finalcompounds of Formula (I).

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, catalysts and scavengers utilized tosynthesize the compounds of the present invention are eithercommercially available or can be produced by organic synthesis methodsknown to one of ordinary skill in the art. Further, the compounds of thepresent invention can be produced by organic synthesis methods known toone of ordinary skill in the art as shown in the following examples.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., LCMS, NMR,CHN. Abbreviations used are those conventional in the art, a list ofwhich is provided at the end of the experimental section.

Preparation 1 Intermediate 1-1 Synthesis of6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To 3,6-dichloropyridazine (4 g, 26.8 mmol) andN,2,2,6,6-pentamethylpiperidin-4-amine (7.32 g, 43.0 mmol) in a 300 mLround bottom flask was added butan-1-ol (67 mL) to give a colorlesssolution. The mixture was heated to 120° C. for 72 h. Butan-1-ol wasremoved using a rotary evaporator. The residue was partitioned betweenwater and DCM, and the water layer was further extracted with DCM. Thecombined organic layers were washed with water and brine, dried overMgSO₄, and concentrated in vacuo. The black crude material was stirredin small amount of EtOAc overnight, and the resulting off-white solidwas collected to provide6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine,Intermediate 1-1 (4.18 g, 14.78 mmol, 55.0% yield). LCMS Rt=0.8 min(condition B), MS (M+1)=283.5. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 7.40(d, J=9.60 Hz, 1H), 7.14 (d, J=9.60 Hz, 1H), 4.96-5.13 (m, 1H), 2.93 (s,3H), 1.59-1.68 (m, 2H), 1.51 (t, J=12.38 Hz, 2H), 1.20 (s, 6H), 1.33 (s,6H).

Preparation 2 Intermediate 1-2 Synthesis of6-chloro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

A mixture of 3,6-dichloropyridazine (6.26 g, 42 mmol) and2,2,6,6-tetramethylpiperidin-4-amine (14.7 mL, 84 mmol) was stirred at120° C. for 1 h, neat. To this crude mixture was added n-butanol (40mL), and the reaction was stirred at 120° C. for 1 h. The crude reactionmixture was cooled to room temperature and diluted in water and CH₂Cl₂.The organic layer was dried over MgSO₄, filtered, and concentrated. Thecrude material was recrystallized from CH₃CN to give6-chloro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine,Intermediate 1-2 (7.3 g) as an off-white solid. LCMS Rt=1.10 min(condition B), MS (M+1)=269.2. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.08(d, J=9.3 Hz, 1H), 6.54 (d, J=9.3 Hz, 1H), 4.53 (d, J=7.6 Hz, 1H),4.05-4.26 (m, 1H), 1.98 (dd, J=12.6, 3.8 Hz, 2H), 1.22 (s, 6H), 1.08 (s,6H), 0.93 (apparent t, J=12.1 Hz, 2H).

Preparation 3 Intermediate 1-3 Synthesis of3-chloro-6-(2,2,6,6-tetramethylpiperidin-4-yloxy)pyridazine

To a solution of 2,2,6,6-tetramethylpiperidin-4-ol (106 mg, 0.67 mmol)in DMF (6.7 mL) was added 60% wt NaH (35 mg, 0.87 mmol). The solutionwas stirred at RT for 30 min, then 3,6-dichloropyridazine (100 mg, 0.67mmol) was added and the reaction was stirred for 1 h. The crude reactionmixture was diluted in EtOAc. The organic layer was washed with water(5×), brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give3-chloro-6-(2,2,6,6-tetramethylpiperidin-4-yloxy)pyridazine,intermediate 1-3 (135 mg). The crude material used without furtherpurification. LCMS Rt=1.22 min (condition B); MS (M+1)=270.2. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.53 (s, 1H), 7.37 (d, J=9.1 Hz, 1H), 6.91(d, J=9.1 Hz, 1H), 5.68-5.78 (m, 1H), 2.20 (dd, J=12.4, 4.0 Hz, 2H),1.32 (s, 6H), 1.27-1.29 (m, 2H), 1.20 (s, 6H).

Preparation 4 Intermediate 1-4 Synthesis of6-chloro-N-methyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine

To a suspension of6-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine,Intermediate 1-5, (4.0 g, 14.1 mmol) in DMF (140 mL) cooled to 0° C. wasadded 60% wt NaH (735 mg, 18.39 mmol) portionwise. The reaction waswarmed to RT and stirred for 60 minutes. After 60 minutes methyl iodide(0.88 mL, 14.1 mmol) was added and the reaction was stirred anadditional 3 h, then slowly quenched with water at room temperature. Thecrude reaction mixture was diluted in EtOAc. The organic layer waswashed with water (5×), brine, dried over MgSO₄, filtered andconcentrated under reduced pressure to give6-chloro-N-methyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine,Intermediate 1-4 (3.98 g). The crude material was carried on withoutfurther purification. LCMS Rt=1.16 min (condition B), MS (M+1)=297.0. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 7.10 (d, J=9.6 Hz, 1H), 6.69 (d, J=9.6Hz, 1H), 4.79-5.00 (m, 1H), 2.86 (s, 3H), 2.22 (s, 3H), 1.61-1.73 (m,2H), 1.48-1.57 (m, 2H), 1.14 (s, 6H), 1.10 (s, 6H).

Intermediate 1-5 Synthesis of6-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine

This material was prepared in two batches.

Batch 1:

A mixture of 1,2,2,6,6-pentamethylpiperidin-4-amine (15.1 g, 89.0 mmol)and 3,6-dichloropyridazine (6.6 g, 44.3 mmol) was heated neat at 120° C.for 30 min. The crude material solidified and was re-suspended inn-butanol (45 mL). The crude mixture was stirred at 120° C. for anadditional 2 h, then heated to 160° C. for 1 h, then cooled, andcombined with batch 2 for workup.

Batch 2:

A mixture of 1,2,2,6,6-pentamethylpiperidin-4-amine (14.2 g, 83 mmol)and 3,6-dichloropyridazine (6.2 g, 41.6 mmol) in n-butanol (10 mL) washeated at 120° C. for 120 min. The crude material solidified and wasre-suspended in n-butanol (15 mL) and heated at 120° C. for 1 h. Thiscrude material was combined with batch 1 for workup and purification.Water and CH₂Cl₂ were added to the combined crude material and theorganic layer was separated, washed with water and brine, dried overMgSO₄, filtered and concentrated. The crude material was recyrstallizedfrom CH₃CN (400 mL) to give6-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine,Intermediate 1-5 (15.5 g, first crop). Recrystallization was repeatedusing CH₃CN to give a 2nd crop of6-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amineIntermediate 1-5 (3.98 g). LCMS Rt=1.10 min (condition B); MS(M+1)=283.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.15 (d, J=9.3 Hz,1H), 6.65 (d, J=9.3 Hz, 1H), 4.70 (d, J=7.3 Hz, 1H), 4.08-4.26 (m, 1H),2.31 (s, 3H), 1.89-2.09 (m, 2H), 1.42 (apparent t, J=12.1 Hz, 2H), 1.21(s, 6H), 1.15 (s, 6H).

Preparation 5 Intermediate 2-1 Synthesis of3-chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine

Step 1: (4-Bromo-3-methoxyphenyl)hydrazine

4-Bromo-3-methoxyaniline (3.0 g, 14.85 mmol) was suspended inconcentrated HCl (50 mL) and the mixture was cooled to 0° C. in theice-water bath. A solution of sodium nitrite (1.23 g, 17.82 mmol) in 10mL water was added very slowly to the reaction mixture. The mixtureturned yellow, then brown with a yellow haze indicating diazotization.The diazonium salt was held at 0° C. for an hour and then a solution oftin(II) chloride dihydrate (10.05 g, 44.5 mmol) in concentrated HCl (20mL) was added very slowly (caution, extremely exothermic). The reactionwas stirred for 2 h at 0° C. then at RT overnight. The reaction wasfiltered and the filter cake was washed with cold H₂O to afford(4-bromo-3-methoxyphenyl)hydrazine as a tan solid (3.1 g, MS: 218[M+H⁺]).

Step 2: 1-(4-Bromo-3-methoxyphenyl)-1H-pyrazole

To a solution of (4-bromo-3-methoxyphenyl)hydrazine (62 g, 245 mmol) inethanol (310 mL) was added tetramethoxypropane (40.2 g, 245 mmol) over afew minutes, and the mixture was heated to an internal temperature of70° C. The mixture was stirred at 70° C. for 1.5 h then slowly cooled toRT. Ethanol was removed in vacuo and the residue was slurried in EtOAc.The residue was neutralized with 1 M aqueous sodium hydroxide (˜700 mL)to cause precipitation. The biphasic mixture was filtered and thefiltrate was extracted with EtOAC, dried over sodium sulfate andconcentrated to provide 30 g of 1-(4-bromo-3-methoxyphenyl)-1H-pyrazoleas a black solid (30 g, MS: 254 [M+H⁺].).

Step 3:1-(3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole

1-(4-bromo-3-methoxyphenyl)-1H-pyrazole (28.5 g, 113 mmol),bis(pinacolato)diboron (42.9 g, 169 mmol), potassium carbonate (15.56 g,113 mmol), and PdCl₂(dppf).CH₂Cl₂ adduct (9.20 g, 11.26 mmol) were addedto a 2 L round bottom flask, followed by addition of dioxane (700 mL).The reaction mixture was purged by N₂ and stirred under N₂ at aninternal temp of 84° C. overnight. The reaction mixture was filteredthrough a disposable filter funnel and concentrated onto silica gel. Themixture was purified using column chromotagraphy (20% EtOAc inheptanes). The desired fractions were collected and concentrated toprovide 13.5 g of1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole.

Step 4: 3-chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine

3,6-Dichloropyridizine (11.99 g, 80 mmol),1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(16.1 g, 53.6 mmol), sodium carbonate (17.06 g, 161 mmol), and1,1′-bis(diphenylphosphino)ferrocene palladium dichloridedichloromethane adduct (3.07 g, 3.75 mmol) were charged to a 3-neck 250mL round bottom flask fitted with a magnetic stir bar and nitrogeninlet. 1,4-Dioxane (274 mL) and deionized water (46 mL) were added andthe reaction mixture was evacuated and backfilled with nitrogen threetimes. The reaction mixture was heated in a teflon heating block to 85°C. for 16 h. After removing the 1,4-dioxane in vacuo, the residue wasslurried in ethyl acetate and filtered through a celite-packed glassfritted funnel. The filtrate was concentrated onto silica gel andpurified on a 330 g Silica gel column, eluting with 10-35% ethyl acetatein heptanes. The product-containing fractions were concentrated down to10% volume, slurried in 3:1 ethyl acetate:heptanes (100 mL), stirred atRT for 1 h, and then filtered to provide 7 g (46%) of3-chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine as a solid.¹H NMR (600 MHz, CHLOROFORM-d) δ 8.12 (dd, J=8.80, 11.30 Hz, 2H), 8.05(d, J=1.88 Hz, 1H), 7.80 (s, 1H), 7.61 (d, J=1.25 Hz, 1H), 7.54 (d,J=9.03 Hz, 1H), 7.35 (dd, J=1.44, 8.22 Hz, 1H), 6.55 (s, 1H), 4.00 (s,3H).

Preparation 6 Intermediate 2-2 Synthesis of2-(6-chloropyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

BCl₃ (1 M in DCM, 91 mL, 91 mmol) was added to a solution of3-chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine (Intermediate2-1, 8.6 g, 30 mmol) in DCM (150 mL) at 0° C. and the reaction wasstirred for 5 h at RT. MeOH (50 mL) was added to the reaction at 0° C.,then the reaction was warmed to RT and the solvent was evaporated underreduced pressure. The crude material was treated with hot CH₃CN thencooled to 5° C. The mixture was filtered and2-(6-chloropyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol Intermediate 2-2(7.6 g, 86%) was afforded as yellow solid. MS [M+H]: 273.2; ¹H NMR (400MHz, DMSO-d6) δ 11.95 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.49 (d, J=9.0Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.80 (d, J=2.0Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.51 (dd, J=8.5, 2.0 Hz, 1H), 6.59 (t,J=2.0 Hz, 1H).

Preparation 7 Intermediate 3-1 Synthesis of7-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol

Bis(pinacolato)diboron (3.13 g, 12.33 mmol), KOAc (3.63 g, 37.0 mmol),and PdCl₂(dppf).CH₂Cl₂ adduct (0.504 g, 0.617 mmol) were added to a 250mL flask containing 7-(benzyloxy)-6-bromonaphthalen-2-ol (2.03 g, 6.17mmol). DMSO (30.8 mL) was then added, and a reflux condenser attached.The reaction mixture was evacuated then filled with N₂ (2×), then heatedat 100° C. overnight. The reaction mixture was cooled to roomtemperature, filtered through celite (pre-packed filter funnel) usingEtOAc, and concentrated in vacuo to a crude oil. Flash chromatography,eluting with 5-30% EtOAc/heptane, afforded the product,7-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol,(58% yield) as a colorless oil. LCMS Rt=1.72 min (condition C), MS(M+1)=377.6. ¹H NMR (400 MHz, METHANOL-d4) δppm 8.07 (s, 1H), 7.68 (t,J=8.91 Hz, 3H), 7.36-7.43 (m, 2H), 7.28-7.34 (m, 1H), 7.09 (s, 1H), 7.02(d, J=2.51 Hz, 1H), 6.92 (dd, J=8.78, 2.51 Hz, 1H), 5.21 (s, 2H), 1.40(s, 12H).

Preparation 8 Intermediate 4-1 Synthesis of(6S)-6-((S)-1-(tert-Butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-ol

Step 1. (S)-Ethyl 2-(tert-butyldimethylsilyloxy)propanoate

To a solution of (S)-ethyl lactate (11.8 g, 100 mmol) in DMF (50 mL) wasadded imidazole (10.2 g, 150 mmol). The mixture was cooled in an icebath and tert-butyldimethylsilyl chloride (15.8 g, 105 mmol) was addedin three portions, at intervals of 30 min between each addition. Thereaction mixture was stirred overnight. The reaction mixture was dilutedwith water (30 mL) and extracted with Et₂O (50 mL×2). The combinedextracts were washed with brine, dried over MgSO₄ and concentrated invacuo. The residue was distilled under vacuum (bp 70-78° C., 0.5 mmHg)to afford 22.07 g (95%) of (S)-ethyl2-(tert-butyldimethylsilyloxy)propanoate: ¹H NMR (400 MHz, CHLOROFORM-d)δ 4.32 (q, J=6.6 Hz, 1H), 4.11-4.25 (m, 2H), 1.40 (d, J=6.6 Hz, 3H),1.29 (t, J=7.1 Hz, 3H), 0.93 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H).

Step 2. (S)-2-(tert-Butyldimethylsilyloxy)propanal

To a solution of (S)-ethyl 2-(tert-butyldimethylsilyloxy)propanoate (6.3g, 27.1 mmol) in CH₂Cl₂ (22 mL) was added 54.2 mL of DIBAL (1.0 M inCH₂Cl₂, 54.2 mmol) over 20 min at −78° C. After stirring for 2 h at −78°C., methanol (3 mL) was added to the solution at the same temperature.The mixture was allowed to warm to RT and saturated aqueous potassiumsodium tartrate (60 mL) was added to the solution. The resulting mixturewas vigorously stirred for 3 h. The mixture was extracted withdichloromethane (30 mL×2), and the combined extracts were washed withbrine (20 mL), dried over sodium sulfate, and concentrated in vacuo. Theresidue was distilled under vacuum (bp 50-52° C., 0.5 mmHg) to afford2.5 g (49%) of (S)-2-(tert-butyldimethylsilyloxy)propanal: ¹H NMR (400MHz, CHLOROFORM-d) δ 9.59 (d, J=1.3 Hz, 1H), 4.07 (dq, J=6.9, 1.3 Hz,1H), 1.26 (d, J=6.9 Hz, 3H), 0.93 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).

Step 3.(SE)-N-(2-(tert-Butyldimethylsilyloxy)propylidene)-1-(4-methoxyphenyl)methanamine

To a solution of (S)-2-(tert-butyldimethylsilyloxy)propanal (2.07 g,11.0 mmol) in dichloromethane (60 mL) was added(4-methoxyphenyl)methanamine (1.51 g, 11.0 mmol) and MgSO₄ (3.97 g, 33.0mmol). After stirring overnight, the mixture was filtered through thecelite and washed with dichloromethane. The solvent was removed underreduced pressure whereuopon 3.38 g (100%) of(S,E)-N-(2-(tert-butyldimethylsilyloxy)propylidene)-1-(4-methoxyphenyl)methanaminewas obtained as a pale yellow oil which was used in the next stepwithout purification: ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.56 (d, J=5.1Hz, 1H), 7.09 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 4.44 (s, 2H),4.24-4.34 (m, 1H), 3.73 (s, 3H), 1.23 (d, J=6.6 Hz, 3H), 0.82 (s, 9H),0.00 (s, 3H), −0.02 (s, 3H).

Step 4.(S)-6-(S)-1-Hydroxyethyl)-1-(4-methoxybenzyl)-2,2-dimethylpiperidin-4-one

To a solution of(S,E)-N-(2-(tert-butyldimethylsilyloxy)propylidene)-1-(4-methoxyphenyl)methanamine(3.38 g, 11 mmol) in dichloromethane (90 mL) was added TMSOTf (2.2 mL,12.1 mmol) and tert-butyldimethyl(4-methylpenta-1,3-dien-2-yloxy)silane(9.35 g, 44 mmol) at 0° C. After stirring for 2 days at 0° C., thereaction mixture was poured into aq. NaHCO₃ solution (100 mL), followedby extraction with dichloromethane (100 mL×2). The combined organiclayers were dried over MgSO₄, and the solvent was evaporated. Theresidue was dissolved in THF (60 mL) and then 41.8 mL of TBAF (1 M inTHF, 41.8 mmol) was added to the solution. The mixture was stirred for12 h, quenched with water (100 mL), extracted with dichloromethane (100mL×2), and the combined extracts were dried over Na₂SO₄. After thesolvent was concentrated in vacuo, the product was purified by columnchromatography (Et2O/Heptane) to give 1.3 g (41%) of(S)-6-((S)-1-hydroxyethyl)-1-(4-methoxybenzyl)-2,2-dimethylpiperidin-4-oneand 1.0 g (31%) of(R)-6-((S)-1-hydroxyethyl)-1-(4-methoxybenzyl)-2,2-dimethylpiperidin-4-one.

(S)-6-((S)-1-hydroxyethyl)-1-(4-methoxybenzyl)-2,2-dimethylpiperidin-4-one

LCMS (m/z, MH⁺): 292.4; ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.13 (d, J=8.6Hz, 2H), 6.74 (d, J=8.6 Hz, 2H), 3.84 (d, J=15.2 Hz, 1H), 3.63-3.70 (m,1H), 3.65 (s, 3H), 3.56 (d, J=15.2 Hz, 1H), 3.36 (qd, J=8.5, 5.9 Hz,1H), 2.93 (dt, J=8.2, 4.8 Hz, 1H), 2.40 (d, J=15.2 Hz, 1H), 2.29-2.36(m, 1H), 2.08-2.17 (m, 2H), 1.17 (s, 3H), 1.14 (s, 3H), 0.81 (d, J=6.1Hz, 3H).

(R)-6-((S)-1-hydroxyethyl)-1-(4-methoxybenzyl)-2,2-dimethylpiperidin-4-one

LCMS (m/z, MH⁺): 292.4; ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.30 (d, J=8.1Hz, 2H), 6.84 (d, J=8.1 Hz, 2H), 4.09 (d, J=16.7 Hz, 1H), 3.82-3.92 (m,1H), 3.74 (s, 3H), 3.26 (d, J=16.7 Hz, 1H), 2.71-2.78 (m, 1H), 2.55-2.66(m, 2H), 2.23 (ddd, J=14.7, 4.5, 2.5 Hz, 1H), 2.15 (dd, J=13.6, 2.5 Hz,1H), 1.70 (br., s, 1H), 1.29 (s, 3H), 1.00 (s, 3H), 0.89 (d, J=6.6 Hz,3H).

Step 5. (S)-6-((S)-1-Hydroxyethyl)-2,2-dimethylpiperidin-4-one

To a solution of(S)-6-((S)-1-hydroxyethyl)-1-(4-methoxybenzyl)-2,2-dimethylpiperidin-4-one(0.28 g, 0.96 mmol) in MeOH (40 mL) was added acetic acid (0.055 mL,0.96 mmol) and palladium hydroxide (0.13 g, 0.96 mmol). After degassing,the mixture was stirred overnight under hydrogen. The mixture wasfiltered through the celite, washed with MeOH (20 mL), and concentratedin vacuo to give 0.11 g (67%) of(S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-one which was used inthe next step without purification.

Step 6.(S)-6-((S)-1-(tert-Butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-one

To a solution of (S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-one(0.11 g, 0.64 mmol) in DMF (3 mL) were added imidazole (0.13 g, 1.93mmol) and TBSCl (0.14 g, 0.96 mmol). The mixture was stirred overnight.The reaction mixture was diluted with water (10 mL) and extracted withEtOAc (20 mL). The extract was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by column chromatography(EtOAc/Heptane) to afford 65 mg (35%) of(S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-one:¹H NMR (400 MHz, CHLOROFORM-d) δ 3.99 (dq, J=6.3, 2.8 Hz, 1H), 2.96-3.04(m, 1H), 2.21-2.32 (m, 3H), 2.13 (d, J=13.1 Hz, 1H), 1.26 (s, 3H), 1.12(d, J=6.1 Hz, 3H), 1.05 (s, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.09 (s,3H).

Step 7.(6S)-6-((S)-1-(tert-Butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-ol

To a solution of(S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-one(42 mg, 0.15 mmol) in MeOH (3 mL) was added NaBH₄ (5.6 mg, 0.15 mmol) at0° C. After the mixture was stirred for 1 h, the mixture was dilutedwith water (5 mL) and extracted with EtOAc (20 mL). The extract waswashed with brine, dried over Na₂SO₄, and concentrated in vacuo.Purification by column chromatography (EtOAc/Heptane) gave 32 mg (76%)of(6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-ol(a 5:1 mixture of diastereomers): ¹H NMR (400 MHz, CHLOROFORM-d) δ4.17-4.27 (m, 1H), 3.71-3.78 (m, 1H), 2.92-3.02 (m, 1H), 1.56-1.67 (m,2H), 1.30-1.37 (m, 2H), 1.25 (s, 3H), 1.07 (d, J=6.1 Hz, 3H), 1.02 (s,3H), 0.83 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H).

General Method 1-1

Representative Procedure for Suzuki Cross-Coupling (ConventionalHeating)

The boronic ester (2 equivalents), Na₂CO₃ (3 equivalents), and Pd(PPh₃)₄(0.1 equivalents) were added to a vial containing the chloropyridazine(1 equivalent). DME (0.2 M) and H₂O (0.8 M) were added and the reactionmixture was evacuated, and filled with N₂ (2×). The reaction was heatedat 90° C. for 18 h, cooled to RT, then filtered through celite(pre-packed funnel) with a MeOH wash. The filtrate was acidified to pH 3using 1 M HCl, then adsorbed onto a MeOH conditioned SCX column. Thecolumn was washed several times (5-7 column volumes) with MeOH, theneluted with 2 N NH₃ in MeOH. The residue was purified by silica gelchromatography to provide the desired product.

General Method 1-2

Representative Procedure for Suzuki Coupling

SiliaCat® DPP-Pd (0.05 equivalents) was added to a microwave vialcontaining a mixture of the chloropyridazine intermediate, such as 1-1,(1 equivalent), boronic acid (1.6 equivalents), and Na₂CO₃ (3equivalents) in wet EtOH (0.2 M). The reaction mixture was sealed, thenheated via microwave irradiation at 130° C. for 35 min. The reactionmixture was filtered through a small celite plug with a MeOH/DCM wash,then concentrated to dryness in vacuo. The resulting brown residue waspartitioned between 5% MeOH/DCM and sat. aq. NaHCO₃ solution. Afterseparation, the aqueous layer was extracted with 5% MeOH/DCM. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated to dryness in vacuo. The resulting residuewas dissolved in MeOH then adsorbed onto a MeOH conditioned SCX column.The column was washed several times with MeOH then eluted with 3 NNH₃/MeOH. Evaporation of the solvent afforded a the crude product. Thecrude product was dissolved in MeOH/DCM then 3 g of Siliabond® DMT(palladium scavenger) was added and the mixture was stirred at RT for 1h. The mixture was filtered then concentrated to dryness in vacuoaffording the desired product.

General Method 1-3

Representative Procedure for Suzuki Coupling Chloropyridazineintermediate, such as 1-1, (1 equivalent), boronic acid reagent (2equivalents), and Na₂CO₃ (3 equivalents) were added to a microwave vial.Pd(PPh₃)₄ (0.1 equivalents) was then added to the reaction mixturefollowed by addition of DME (0.2 M) and H₂O (0.8 M). The reactionmixture was sealed, then evacuated and filled with N₂ (2×), and heatedvia microwave irradiation at 125° C. for 30 min. The reaction mixturewas filtered through celite and washed with DCM. The resulting filtratewas washed with 1 M aq. Na₂CO₃ solution. The organic layer was driedover MgSO₄, filtered, and concentrated to afford the crude product. Thecrude product was purified by flash chromatography affording the productas an off-white solid.

General Method 1-4

Representative Procedure for Suzuki Coupling

Boronic ester (0.36 mmol), pyridazine intermediate (0.36 mmol), Na₂CO₃(1.08 mmol), DME (0.58 mL), and H₂O (0.14 mL) were added to a 5 mLmicrowave vial. The vial was degassed for 5 min with N₂, thenPdCl₂(dppf)CH₂Cl₂ adduct (29.4 mg, 0.04 mmol) was added. The reactionmixture was heated via microwave irradiation at 120° C. for 45 min. Thecrude mixture was diluted with EtOAc and filtered through celite, thenconcentrated in vacuo. Flash chromatography, eluting with 0-100%EtOAc/heptane, afforded the product.

General Method 2-1

Representative Procedure for Boronate Ester Formation.

Bis(pinacolato) diboron (12.3 mmol), KOAc (37.0 mmol), andPdCl₂(dppf).CH₂Cl₂ (0.617 mmol) were added to a 250 mL round bottomflask containing an aryl bromide (6.17 mmol). DMSO (31 mL) was thenadded, and reflux condenser attached. The reaction mixture was evacuatedthen filled with N₂ (2×), then heated at 100° C. overnight. The reactionmixture was cooled to RT, then filtered through celite (pre-packedfilter funnel) using EtOAc, and concentrated in vacuo to a crude oil.Flash chromatography, eluting with 5-30% EtOAc/heptane, afforded theproduct.

General Method 3-1

Representative Procedure for Methoxy Deprotection (Thiophenol)

Thiophenol (1 equivalent) and potassium carbonate (1 equivalent) wereadded to the methoxy substrate in NMP (0.2 M) and the reaction wasstirred at 190° C. for 15 min in a Biotage® Initiator microwave reactor.The reaction mixture was purified by catch and release using SiliaBondPropylsulfonic Acid® (2 g, MeOH as eluent and a 2 N ammonia solution inMeOH to release the material). After evaporation, the material waspurified via reverse phase HPLC.

General Method 3-2

Representative Procedure for Methoxy Deprotection (BBr₃)

The methoxy substrate (1 equivalent) was dissolved in CH₂Cl₂ (0.03 M)and cooled in an ice bath. A 1 M solution of BBr₃ in CH₂Cl₂ (3equivalents) was added dropwise. The crude reaction mixture as stirredat RT overnight then diluted with CH₂Cl₂ and water. The organic layerwas diluted in EtOAc and washed with sat NaHCO₃ aq (2×), water, brineand dried over Na₂SO₄. The crude product was purified via HPLC, columnchromotography or recystallization.

General Method 3-3

Representative Procedure for Methoxy Deprotection (LiI, Collidine)

To a solution of the methoxy substrate (1 equivalent) in 2,4,6 collidine(0.03 M, dried over MgSO₄, and filtered), was added anhydrous LiI (9equivalents). The reaction was stirred at 170° C. for 4 hrs, then cooledand diluted with small amounts of MeOH, EtOAc and H₂O. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was purified via HPLC.

General Method 4-1

Representative Procedure for Hydrogenolysis of Benzyl Group.

In a 25 mL round-bottomed flask, Pd/C (1.6 mg, 0.016 mmol) or Pd(OH)₂(2.2 mg, 0.016 mmol) was added to the benzyl-protected substrate (75 mg,0.155 mmol) in EtOH (1.5 mL). 1 M HCl solution (0.25 mL, 0.25 mmol) wasadded and the reaction vessel was evacuated. H₂ was bubbled through thesolution for 5 min, then reaction was stirred under H₂ at RT. After 18h, the reaction mixture was filtered through celite and washed withMeOH/DCM. The solvent was removed in vacuo and the crude material wasdissolved in MeOH, and purified by preparative HPLC (10-30% ACN/H₂O with0.1% TFA). The residue was dissolved in MeOH/DCM, acidified to ca. pH 3using 1 M HCl then adsorbed onto a MeOH conditioned SCX column. Thecolumn was washed several times (3-4 column volumes) with MeOH theneluted with 2 N NH₃/MeOH. Evaporation of the solvent afforded thedesired product.

General Method 4-2

Representative Procedure for Hydrogenation

To a 25 mL round-bottomed flask containing 10% Pd/C (0.026 mmol), wasadded the substrate (0.52 mmol) in MeOH (2.5 mL). H₂ was bubbled throughthe solution for 5 min, then reaction was stirred under H₂ at 55 psi atRT. After 18 h, the reaction mixture was filtered through celite andwashed with MeOH. The solvent was removed in vacuo. The resulting oilwas dissolved in MeOH then adsorbed onto a MeOH conditioned SCX column.The column was washed several times (5-7 column volumes) with MeOH theneluted with 2 N NH₃ in MeOH to provide the desired product.

General Method 5-1

Representative Procedure for Phenol Alkylation

Cs₂CO₃ (1.489 mmol) was added to a solution of the phenol (1.489 mmol)in acetone (15 mL) at RT. The reaction mixture was stirred for 5 minthen the bromide (682 mg, 2.98 mmol) was added all at once, followed byaddition of NaI (446 mg, 2.98 mmol). The reaction mixture was stirred at60° C. overnight, filtered with acetone, then concentrated in vacuo. Theresulting residue was partitioned between Et₂O (60 mL) and water (20mL). After separation, the organic layer was washed with saturated aq.sodium sulfite solution (20 mL), 2 M Na₂CO₃, and brine. The organiclayer was then dried over MgSO₄, filtered, and concentrated in vacuo.Flash chromatography afforded the desired product.

General Method 6-1

Representative Procedure for SnAr Reaction

Intermediate 2-2 (50 mg, 0.174 mmol), tert-butylpiperazine-1-carboxylate (59 mg, 0.314 mmol), DIPEA (0.06 mL, 0.349mmol), and n-butanol (0.1 mL) were combined in a 4 mL reaction vial andheated to 120° C. overnight. The reaction was cooled to RT and EtOAc wasadded. The white solid was filtered and washed with EtOAc, dissolved inDCM and washed with H₂O. The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo to afford desired product.Purification by flash column or HPLC provided the desired compound.

Example 1-1 Synthesis of6-(naphthalen-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a 2 mL microwave vial was added6-chloro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineIntermediate 1-2 (100 mg, 0.37 mmol), naphthalen-2-ylboronic acid (96mg, 0.56 mmol), Na₂CO₃ (118 mg, 1.17 mmol), water (0.25 mL), DME (1 mL),and PdCl₂(dppf).CH₂Cl₂ (30 mg, 0.037 mmol). The reaction vessel wassealed and heated in a microwave at 120° C. for 45 mins. The crudemixture was diluted with EtOAc, then the organic layer was washed withwater, brine, dried over MgSO₄, filtered and concentrated. The crudeproduct was purified via silica chromatography to give6-(naphthalen-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(86 mg). LCMS Rt=1.39 min (condition B); MS (M+1)=361.3. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.30 (s, 1H), 8.12 (dd, J=8.6, 1.8 Hz, 1H),7.86 (d, J=8.8 Hz, 1H), 7.76-7.84 (m, 2H), 7.67 (d, J=9.3 Hz, 1H),7.37-7.48 (m, 2H), 6.69 (d, J=9.1 Hz, 1H), 4.82 (br. m, 1H), 4.31-4.51(m, 2H), 2.07 (dd, J=12.9, 3.5 Hz, 2H), 1.35 (s, 6H), 1.22 (s, 6H).

The following compounds were prepared using similar procedures as inExample 1-1:

LCMS M + 1, Example Compound Rt, conditions ¹H NMR 400 MHz 1-2

381.3 0.58 min Q CHLOROFORM-d δ ppm 7.88-7.92 (m, 1H), 7.78-7.83 (m,1H), 7.71 (d, J = 9.6 Hz, 1H), 7.67 (s, 1H), 7.34-7.44 (m, 2H), 6.87 (d,J = 9.6 Hz, 1H), 5.06- 5.34 (m, 1H), 3.05 (s, 3H), 1.74 (dd, J = 12.3,3.2 Hz, 2H), 1.43-1.50 (m, 2H), 1.42 (s, 6H), 1.23 (s, 6H) 1-3

327.2 0.42 min Q CHLOROFORM-d δ ppm 13.64 (br. s, 1H), 7.85 (d, J = 9.6Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.30-7.35 (m, 1H), 7.10 (d, J = 8.1Hz, 1H), 6.90-6.99 (m, 1H), 6.84 (d, J = 9.3 Hz, 1H), 4.66 (d, J = 6.3Hz, 1H), 4.17-4.46 (m, 1H), 2.13 (dd, J = 12.3, 3.2 Hz, 2H), 1.38 (s,6H), 1.23 (s, 6H), 1.03-1.16 (m, 2H) 1-4

406.3 0.55 min Q DMSO-d6 δ ppm 8.34 (d, J = 1.0 Hz, 1H), 8.22 (d, J =8.3 Hz, 1H), 8.11 (d, J = 9.6 Hz, 1H), 8.06 (s, 1H), 7.72 (dd, J = 8.3,1.8 Hz, 1H), 7.20 (d, J = 9.9 Hz, 1H), 5.05-5.23 (m, 1H), 2.95 (s, 3H),1.51 (dd, J = 11.9, 3.5 Hz, 2H), 1.38- 1.47 (m, 2H), 1.25 (s, 6H), 1.09(s, 6H) 1-5

362.2 0.41 min Q CHLOROFORM-d δ ppm 9.59 (d, J = 2.3 Hz, 1H), 8.74 (d, J= 2.0 Hz, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H),7.72-7.83 (m, 2H), 7.57-7.65 (m, 1H), 6.79 (d, J = 9.3 Hz, 1H), 4.71 (d,J = 7.6 Hz, 1H), 4.37-4.53 (m, 1H), 2.16 (dd, J = 12.6, 3.8 Hz, 2H),1.38 (s, 6H), 1.22 (s, 6H), 1.06-1.16 (m, 2H) 1-6

368.1 0.56 min Q CHLOROFORM-d δ ppm 7.90-7.96 (m, 1H), 7.88 (d, J = 9.1Hz, 1H), 7.81-7.86 (m, 1H), 7.79 (s, 1H), 7.33-7.47 (m, 2H), 7.01 (d, J= 9.3 Hz, 1H), 5.77-6.02 (m, 1H), 2.28 (dd, J = 12.5, 4.2 Hz, 2H), 1.39(s, 6H), 1.31-1.38 (m, 2H), 1.27 (s, 6H) 1-7

341.3 1.02 min B METHANOL-d4 δ ppm 8.09 (d, J = 9.9 Hz, 1H), 7.74 (dd, J= 8.0, 1.4 Hz, 1H), 7.30 (d, J = 9.9 Hz, 1H), 7.21-7.27 (m, 1H),6.88-6.98 (m, 2H), 4.99-5.13 (m, 1H), 3.00 (s, 3H), 1.67 (dd, J = 12.6,3.8 Hz, 2H), 1.48-1.61 (m, 2H), 1.37 (s, 6H), 1.22 (s, 6H) 1-8

391.0 0.48 min Q METHANOL-d4 δ ppm 8.23 (d, J = 1.0 Hz, 1H), 8.00 (dd, J= 8.6, 1.8 Hz, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H),7.73 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 9.6 Hz, 1H), 7.13 (s, 1H), 7.07-7.12 (m, 1H), 5.13-5.31 (m, 1H), 2.99 (s, 3H), 1.69 (dd, J = 12.6, 3.5Hz, 2H), 1.52-1.62 (m, 2H), 1.39 (s, 6H), 1.23 (s, 6H) 1-9

367.4 0.54 min Q CHLOROFORM-d δ ppm 7.89-7.83 (m, 1H), 7.80-7.75 (m,1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.38-7.31 (m, 2H), 6.67 (d, J = 9.60Hz, 1H), 4.56 (d, J = 6.57 Hz, 1H), 4.48-4.36 (m, 1H), 2.13 (dd, J =12.63, 3.54 Hz, 2H), 1.35 (s, 6H), 1.19 (s, 6H), 1.06-1.05 (m, 2H) 1-10

363.1 0.43 min Q DMSO-d6 δ ppm 9.43 (s, 1H), 8.84- 8.90 (m, 1H),8.55-8.59 (m, 2H), 8.38 (d, J = 9.29 Hz, 1H), 8.12 (d, J = 8.78 Hz, 1H),7.90 (d, J = 5.77 Hz, 1H), 7.35 (d, J = 9.29 Hz, 1H), 5.75 (tt, J =11.26, 4.05 Hz, 1H), 2.12 (d, J = 8.78 Hz, 2H), 1.26 (br. s, 8H), 1.12(br. s, 6H) 1-11

363.1 0.41 min Q METHANOL-d4 δ ppm 9.33 (s, 1H), 8.55 (s, 1H), 8.52 (d,J = 5.77 Hz, 1H), 8.40 (dd, J = 8.66, 1.63 Hz, 1H), 8.25- 8.31 (m, 2H),7.97 (d, J = 5.77 Hz, 1H), 7.29 (d, J = 9.29 Hz, 1H), 5.85 (tt, J =11.23, 4.20 Hz, 1H), 2.28 (dd, J = 12.80, 4.02 Hz, 2H), 1.47 (t, J =11.92 Hz, 2H), 1.40 (s, 6H), 1.28 (s, 6H) 1-12

376.2 0.46 min Q DMSO-d6 δ ppm 8.94 (dd, J = 4.27, 1.76 Hz, 1H), 8.58(d, J = 0.75 Hz, 1H), 8.35-8.46 (m, 2H), 8.18 (d, J = 9.54 Hz, 1H), 8.08(d, J = 8.53 Hz, 1H), 7.55 (dd, J = 8.28, 4.27 Hz, 1H), 7.19 (d, J =9.79 Hz, 1H), 5.17 (br. s, 1H), 2.96 (s, 3H), 1.35-1.59 (m, 4H), 1.27(s, 6H), 1.10 (s, 6H) 1-13

376.7 0.45 min Q DMSO-d6 δ ppm 8.91 (dd, J = 4.02, 1.76 Hz, 1H), 8.62(d, J = 2.01 Hz, 1H), 8.52 (dd, J = 8.78, 2.01 Hz, 1H), 8.45 (dd, J =8.41, 0.88 Hz, 1H), 8.11 (dd, J = 9.29, 5.27 Hz, 2H), 7.58 (dd, J =8.28, 4.27 Hz, 1H), 7.20 (d, J = 9.79 Hz, 1H), 5.20 (br. s, 1H), 3.35(s, 1H), 2.95 (s, 3H), 1.49-1.57 (m, 2H), 1.39-1.48 (m, 2H), 1.26 (s,6H), 1.09 (s, 6H) 1-14

376.24 0.42 min Q DMSO-d6 δ ppm 9.40 (s, 1H), 8.76 (s, 1H), 8.48-8.58(m, 2H), 8.14 (d, J = 9.54 Hz, 1H), 8.07 (d, J = 8.78 Hz, 1H), 7.86 (d,J = 5.77 Hz, 1H), 7.21 (d, J = 9.79 Hz, 1H), 5.21 (br. s, 1H), 3.35 (s,1H), 2.95 (s, 3H), 1.49-1.58 (m, 2H), 1.39-1.48 (m, 2H), 1.27 (s, 6H),1.10 (s, 6H) 1-15

376.25 0.40 min Q METHANOL-d4 δ ppm 9.28 (s, 1H), 8.46-8.50 (m, 2H),8.38 (dd, J = 8.66, 1.63 Hz, 1H), 8.24 (d, J = 8.78 Hz, 1H), 8.13 (d, J= 9.54 Hz, 1H), 7.93 (d, J = 5.77 Hz, 1H), 7.30 (d, J = 9.54 Hz, 1H),5.54 (dt, J = 10.73, 5.55 Hz, 1H), 3.05 (s, 3H), 1.91-1.98 (m, 4H), 1.63(s, 6H), 1.48 (s, 6H) 1-16

0.34 min 365.2 Q DMSO-d6 δ ppm 9.18-9.21 (m, 1H), 7.87-7.99 (m, 3H),7.58-7.66 (m, 2H), 7.15 (d, J = 9.60 Hz, 1H), 5.07-5.16 (m, 1H), 2.94(s, 3H), 1.50-1.64 (m, 2H), 1.45 (br. s, 2H), 1.28 (br. s, 6H), 1.11(br. s, 6H) 1-17

402.2 0.55 min Q CHLOROFORM-d6 δ ppm 9.21 (d, J = 1.52 Hz, 1H),8.43-8.56 (m, 1H), 8.08 (dd, J = 8.34, 1.26 Hz, 2H), 7.79- 7.93 (m, 1H),7.69 (d, J = 9.60 Hz, 1H), 7.47-7.54 (m, 2H), 7.44 (d, J = 7.58 Hz, 1H),6.90 (d, J = 9.60 Hz, 1H), 5.16-5.10 (m, 1H), 3.05 (s, 3H), 1.75 (dd, J= 12.13, 3.54 Hz, 2H), 1.46 (t, J = 12.13 Hz, 2H), 1.39 (s, 6H), 1.21(s, 6H) 1-18

391.26 0.54 min Q CHLOROFORMA-d δ ppm 8.74-8.87 (m, 1H), 8.40 (d, J =8.59 Hz, 1H), 7.53 (d, J = 9.60 Hz, 1H), 7.45-7.50 (m, 2H), 7.26-7.36(m, 1H), 6.78 (d, J = 10.11 Hz, 1H), 6.28 (t, J = 2.27 Hz, 2H),5.04-4.98 (m, 1H), 2.94 (s, 3H), 1.62 (d, J = 3.54 Hz, 2H), 1.35 (br. s,2H), 1.28 (s, 6H), 1.10 (s, 6H) 1-19

392.25 0.52 min Q CHLOROFORM-d δ ppm 8.87 (d, J = 1.52 Hz, 1H), 8.52 (d,J = 3.54 Hz, 1H), 8.40 (dd, J = 8.59, 2.02 Hz, 1H), 7.99 (d, J = 8.59Hz, 1H), 7.66 (d, J = 1.01 Hz, 1H), 7.54 (d, J = 9.60 Hz, 1H), 6.79 (d,J = 9.60 Hz, 1H), 6.39 (dd, J = 2.53, 1.52 Hz, 1H), 5.12-4.98 (m, 1H),2.94 (s, 3H), 1.64 (dd, J = 12.63, 3.54 Hz, 2H), 1.36 (br. s, 2H), 1.24-1.33 (m, 6H), 1.11 (br. s, 6H) 1-20

377.2 0.88 min Q CHLOROFORM-d δ ppm 10.03 (s, 1H), 8.36 (d, J = 9.60 Hz,1H), 7.92-8.12 (m, 2H), 7.64 (ddd, J = 7.58, 5.31, 1.77 Hz, 2H), 6.87(d, J = 9.60 Hz, 1H), 5.12- 5.06 (m, 1H), 3.00 (s, 3H), 1.66 (dd, J =12.38, 3.28 Hz, 2H), 1.38 (m, 2H), 1.30 (s, 6H), 1.11 (s, 6H) 1-21

376.3 0.50 min Q DMSO-d6 δ ppm 9.60 (d, J = 2.53 Hz, 1 H), 8.87 (d, J =2.02 Hz, 1H), 8.02- 8.13 (m, 3H), 7.76 (ddd, J = 8.34, 6.82, 1.52 Hz,1H), 7.59-7.68 (m, 1H), 7.18 (d, J = 10.11 Hz, 1H), 5.09-5.21 (m, 1H),2.97 (s, 3 H), 1.56 (dd, J = 12.38, 3.79 Hz, 2H), 1.45 (t, J = 12.13 Hz,2H), 1.26-1.32 (m, 6H) 1.10 (s, 6H)

Example 1-22 Synthesis ofN-methyl-6-(phthalazin-6-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

A mixture of 6-bromophthalazine (0.11 g, 0.50 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(0.16 g, 0.58 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.14 g,0.55 mmol), potassium acetate (0.15 g, 1.5 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.04 g, 0.05 mmol) in dioxane (3 mL) was heated at80° C. for 3 h. Potassium carbonate (0.20 g, 1.5 mmol) and water (0.4mL) were added and the mixture was stirred for 48 h at 90° C. Aftercooling, the reaction was purified by solid phase extraction (SiliaBondCarbonate®, MeOH as eluent). After evaporation of the solvent underreduced pressure, the material afforded was purified via reverse phasepreparative HPLC using 5 to 95% acetonitrile in water modified with 3%n-PrOH. LCMS: Rt=0.43 min [M+H] (LCMS method Q); 377.245; ¹H NMR (400MHz, DMSO-d6) δ 9.74-9.62 (m, 2H), 8.75 (s, 1H), 8.74 (dd, J=8.5, 2.0Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.12 (d, J=9.5 Hz, 1H), 7.19 (d, J=9.5Hz, 1H), 5.19 (tt, J=12.0, 3.5 Hz, 1H), 2.98 (s, 3H), 1.56 (dd, J=12.0,3.5 Hz, 2H), 1.45 (t, J=12.0 Hz, 2H), 1.27 (s, 6H), 1.10 (s, 6H).

The following compounds are prepared using similar procedures as inExample 1-1 utilizing high throughput parallel solution phase synthesistechnology.

LCMS M + 1, Rt Example Product conditions 2-1

353.2 0.51 min Q 2-2

368.2 1.26 min B 2-3

366.3 2.87 min B

The following final compounds were prepared using similar procedures asin Example 1-1, followed by methoxy deprotection as outlined in GENERALMETHODS 3-1 and 3-2 when appropriate.

LCMS M + 1, Rt, Example Compound conditions ¹H NMR 400 MHz 3-1

391.1 0.56 min Q DMSO-d6 δ ppm 13.33( br. s, 1H), 8.51 (s, 1H), 8.37 (d,J = 9.9 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H),7.37-7.48 (m, 2H), 7.30 (s, 1H), 7.27-7.34 (m, 1H), 4.92-5.14 (m, 1H),2.98 (s, 3H), 1.54 (dd, J = 11.9, 3.3 Hz, 2H), 1.45 (m, J = 12.1 Hz,2H), 1.27 (s, 6H), 1.10 (s, 6H) 3-2

389.1 1.30 min B DMSO-d6 δ ppm 14.05 (br. s, 1H), 8.20 (d, J = 9.9 Hz,1H), 7.91 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 9.9 1H), 7.01 (d, J = 2.0Hz, 1H), 6.97 (dd, J = 8.5, 2.1 Hz, 1H), 4.75-4.95 (m, 1H), 2.97 (s,3H), 2.20 (s, 3H), 1.62-1.74 (m, 2H), 1.49- 1.60 (m, 2H), 1.13 (s, 6H),1.11 (s, 6H) 3-3

377.3 1.06 min B CHLOROFORM-d δ ppm 13.42 (br. s, 1H), 8.12 (s, 1H),8.04 (d, J = 9.6 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.3 Hz,1H), 7.41-7.49 (m, 1H), 7.43 (s, 1H), 7.31-7.35 (m, 1H), 6.90 (d, J =9.6 Hz, 1H), 4.75 (br. s, 1H), 4.33- 4.51 (m, 1H), 2.15 (dd, J = 12.3,2.1 Hz, 2H), 1.42 (s, 6H), 1.27 (s, 6H), 1.10- 1.19 (m, 2H) 3-4

375.1 0.55 min Q DMSO-d6 δ ppm 14.36 (br. s, 1H), 8.10 (d, J = 9.6 Hz,1H), 7.84 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.03 (d, J =9.6 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 8.5, 2.1 Hz, 1H),4.14- 4.36 (m, 1H), 2.20 (s, 3H), 1.83-1.96 (m, 2H), 1.25-1.35 (m, 2H),1.10 (s, 6H), 1.08 (s, 6H) 3-5

366.0 0.51 min Q CHLOROFORM-d δ ppm 7.91 (d, J = 2.02 Hz, 1H), 7.83 (d,J = 9.85 Hz, 1 H), 7.54 (dd, J = 8.59 , 2.02 Hz, 1H), 7.12 (d, J = 8.59Hz, 1H), 7.06 (d, J = 9.85 Hz, 1H), 5.06 (br. s, 1H), 3.05 (s, 3H), 1.73(dd, J = 12.51, 3.41 Hz, 2 H), 1.43-1.58 (m, 3H), 1.41 (s, 6H), 1.25 (s,6H) 3-6

378.21 0.57 min Q CHLOROFORM-d δ ppm 8.00-8.21 (m, 2H), 7.69 (d, J =8.08 Hz, 1H), 7.61 (d, J = 8.08 Hz, 1H), 7.28-7.43 (m, 2H), 7.18-7.25(m, 1H), 7.04 (d, J = 9.60 Hz, 1H), 5.72 (tt, J = 10.99, 4.42 Hz, 1H),2.17 (dd, J = 12.63, 4.04 Hz, 2H), 1.48 (br. s, 2H), 1.36 (br. s, 6H),1.28 (br. s, 6H) 3-7

409.1 0.58 min Q CHLOROFORM-d δ ppm 14.41 (br. s, 1H), 7.87 (d, J =10.04 Hz, 1H), 7.82 (d, J = 1.76 Hz, 1H), 7.50 (dd, J = 8.53, 1.76 Hz,1H), 7.12 (d, J = 8.53 Hz, 1H), 7.03 (d, J = 9.79 Hz, 1H), 4.99 (t, J =11.17 Hz, 1H), 3.03 (s, 3H), 1.72 (dd, J = 12.55, 3.26 Hz, 2H), 1.45 (t,J = 12.30 Hz, 2H), 1.38 (s, 6H), 1.22 (s, 6H) 3-8

359.1 0.51 min Q CHLOROFORM-d δ ppm 14.13 (br. s, 1H), 7.82 (d, J = 9.79Hz, 1H), 7.36 (d, J = 8.03 Hz, 1H), 7.10 (ddd, J = 10.60, 8.09, 1.38 Hz,1H), 7.01 (d, J = 10.04 Hz, 1H), 6.83 (td, J = 8.09, 4.89 Hz, 1H), 4.97(br. s, 1H), 3.03 (s, 3H), 1.72 (dd, J = 12.30, 3.01 Hz, 2H), 1.40 (br.s, 8H), 1.23 (br. s, 6H) 3-9

401.3 0.48 min Q DMSO-d6 δ ppm 13.86 (br. s, 1H), 8.12 (d, J = 9.60 Hz,1H), 7.23 (d, J = 10.11 Hz, 1H), 6.17 (d, J = 2.53 Hz, 1H), 6.15 (d, J =2.53 Hz, 1H), 4.95-4.80 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 2.93 (s,3H), 1.61-1.44 (m, 4H), 1.28 (s, 6H), 1.13 (br. s, 6H) 3-10

401.3 0.48 min Q DMSO-d6 δ ppm 13.38 (s, 1H), 8.11 (d, J = 10.10 Hz,1H), 7.33 (s, 1H), 7.26 (d, J = 10.11 Hz, 1H), 6.56 (s, 1H), 4.95- 4.83(m, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 2.94 (s, 3H), 1.58-1.51 (m, 2H),1.43 (t, J = 12.13 Hz, 2H), 1.26 (s, 6H), 1.09 (s, 6H) 3-11

371.7 0.52 min Q DMSO-d6 δ ppm 13.91 (s, 1H), 8.18 (d, J = 10.04 Hz,1H), 7.82 (d, J = 8.53 Hz, 1H), 7.45 (d, J = 10.04 Hz, 1H), 6.54-6.48(m, 2H), 5.07 (t, J = 12.30 Hz, 1H), 3.77 (s, 3H), 2.96 (s, 3H), 1.99(t, J = 12.80 Hz, 2H), 1.75 (d, J =11.04 Hz, 1H), 1.53 (s, 6H), 1.47 (s,6H) 3-12

377.2 0.56 min Q DMSO-d6 δ ppm 8.14 (d, J = 9.60 Hz, 1H), 7.94 (dd, J =12.13, 9.09 Hz, 1H), 7.33 (d, J = 10.11 Hz, 1H), 6.95 (dd, J = 12.13,7.07 Hz, 1H), 5.08-4.88 (m, 1H), 2.96 (s, 3H), 1.63-1.48 (m, 4H), 1.31(s, 6H), 1.17 (br. s, 6H)

Example 4-1 Synthesis of5-fluoro-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol

Step 1:6-(2-(Benzyloxy)-4-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Intermediate 1-1 and (2-(benzyloxy)-4-fluorophenyl)boronic acid werereacted according to GENERAL METHOD 1-1 for Suzuki coupling. A tan solid(94% yield) was obtained after SCX purification. No furtherchromatography was needed. MS (M+1)=449.2. ¹H NMR (400 MHz, DMSO-d6) δppm 7.79-7.67 (m, 2H) 7.43-7.27 (m, 5H) 7.10 (dd, J=11.37, 2.27 Hz, 1H)6.99 (d, J=9.60 Hz, 1H) 6.88 (td, J=8.46, 2.27 Hz, 1H) 5.20 (s, 2H)5.10-4.98 (m, 1H) 2.90 (s, 3H) 1.51 (dd, J=12.13, 3.54 Hz, 2H) 1.41 (t,J=12.13 Hz, 2H) 1.24 (s, 6H) 1.11 (s, 1H) 1.08 (s, 6H)

Step 2:5-Fluoro-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol

Following GENERAL METHOD 4-1, Pd/C (10% wt, 47.0 mg, 0.044 mmol) wasadded to a solution of6-(2-(benzyloxy)-4-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(198 mg, 0.441 mmol) in MeOH (2 mL)/EtOAc (2 mL) at RT. The reactionmixture was evacuated and filled with H₂ (2×), then stirred under H₂atmosphere for 4 h and filtered through celite using MeOH. The filtratewas concentrated in vacuo affording a yellow oil, which was redissolvedin DCM and concentrated in vacuo affording the title compound as ayellow solid (129 mg, 82% yield). LCMS Rt=0.49 min (LCMS method Q); MS(M+1)=359.2. ¹H NMR (400 MHz, DMSO-d6) δ ppm 14.10 (br. s, 1H), 8.11 (d,J=9.60 Hz, 1H), 7.83-7.92 (m, 1H), 7.32 (d, J=10.11 Hz, 1H), 6.67-6.77(m, 2H), 4.83-4.98 (m, 1H), 2.95 (s, 3H), 1.54 (dd, J=12.13, 3.54 Hz,2H), 1.43 (t, J=12.13 Hz, 2H), 1.25 (s, 6H), 1.09 (s, 6H).

Example 5-1 Synthesis of3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile

Step 1:3-Methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile

To a flask containing6-(4-chloro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(1.1 g, 2.88 mmol), Pd₂(dba)₃ (0.26 g, 0.29 mmol), dppf (0.32 g, 0.58mmol), zinc dust (75 mg, 1.15 mmol), and zinc cyanide (1.0 g, 8.63 mmol)was added DMA (8.99 mL). The reaction was stirred at 150° C. for 18 h.The crude reaction mixture was cooled to RT, then diluted with EtOAc andfiltered through celite. The filtrate was washed with 1 M NaOH (4×),water (6×), and brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude product waspurified via column chromatography to give3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile(1.1 g). LCMS Rt=1.02 min (condition B); MS (M+1)=380.4. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.09 (d, J=8.1 Hz, 1H), 7.80 (d, J=9.6 Hz, 1H),7.38 (dd, J=7.8, 1.5 Hz, 1H), 7.21 (d, J=1.5 Hz, 1H), 6.81 (d, J=9.6 Hz,1H), 5.12-5.28 (m, 1H), 3.90 (s, 3H), 3.00 (s, 3H), 1.71 (dd, J=12.5,3.4 Hz, 2H), 1.42-1.51 (m, 2H), 1.38 (s, 6H), 1.23 (s, 6H).

Step 2:3-Hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile

Following GENERAL METHOD 3-3 for methoxy deprotection using LiI andcollidine,3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrilewas prepared. LCMS Rt=0.52 min (LCMS method Q); MS (M+1)=366.2. NMR: ¹HNMR (400 MHz, DMSO-d6) δ ppm 8.27 (d, J=9.85 Hz, 1H), 8.08 (d, J=8.08Hz, 1H), 7.28-7.46 (m, 3H), 4.99 (br. s, 1H), 2.97 (s, 3H), 1.37-1.60(m, 4H), 1.25 (s, 6H), 1.08 (s, 6H).

Example 6-1 Synthesis of1-allyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

Step 1:6-(6-(Allyloxy)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a solution of6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(208 mg, 0.53 mmol) in DMF (5.3 mL) was added 60% wt NaH (47 mg, 1.17mmol) followed by allyl iodide (54 μL, 0.59 mmol). The reaction wasstirred at RT for 10 min. The crude reaction mixture was diluted withEtOAc. The organic layer was washed with water (5×) and brine, thendried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude product was purified via HPLC to give6-(6-(allyloxy)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(85 mg). LCMS Rt=1.46 min (condition B); MS (M+1)=431.1. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.37 (d, J=1.5 Hz, 1H), 8.20 (dd, J=8.6, 1.8Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.79 (d, J=9.9Hz, 1H), 7.20-7.25 (m, 1H), 7.19 (d, J=2.3 Hz, 1H), 6.92 (d, J=9.6 Hz,1H), 6.09-6.23 (m, 1H), 5.51 (dd, J=17.2, 1.5 Hz, 1H), 5.36 (dd, J=10.5,1.4 Hz, 1H), 5.16-5.31 (m, 1H), 4.66-4.74 (m, 2H), 3.03 (s, 3H), 1.76(dd, J=12.5, 3.4 Hz, 2H), 1.45-1.53 (m, 2H), 1.41 (s, 6H), 1.24 (s, 6H).

Step 2:1-Allyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

A flask containing6-(6-(allyloxy)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(40 mg, 0.09 mmol) was placed into a preheated oil bath at 220° C. for10 min. After 10 min, the flask was allowed to cool to RT. The crudeproduct was purified via HPLC (XBridge C8, H₂O (0.1% NH₄OH aq. asmodifier/CH₃CN) to give1-allyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(25 mg). LCMS Rt=1.20 min (condition B); MS (M+1)=431.0. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.40 (d, J=1.8 Hz, 1H), 8.21 (dd, J=9.0, 1.9Hz, 1H), 8.01 (d, J=9.1 Hz, 1H), 7.71-7.86 (m, 2H), 7.17 (d, J=8.8 Hz,1H), 6.92 (d, J=9.6 Hz, 1H), 6.03-6.21 (m, 1H), 5.18-5.39 (m, 1H), 5.15(dd, J=6.9, 1.6 Hz, 1H), 5.11 (dd, J=13.9, 1.8 Hz, 1H), 3.88 (d, J=5.6Hz, 2H), 3.03 (s, 3H), 1.76 (dd, J=12.4, 3.3 Hz, 2H), 1.43-1.57 (m, 2H),1.41 (s, 6H), 1.25 (s, 6H).

Example 7-1 Synthesis of6-(benzo[b]thiophen-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine

Step 1: 3-(Benzo[b]thiophen-2-yl)-6-chloropyridazine

To 3,6-dichloropyridazine (4.18 g, 28.1 mmol) and Na₂CO₃ (8.93 g, 84mmol) in DME (100 mL) and water (25 mL) was addedbenzo[b]thiophen-2-ylboronic acid (5 g, 28.1 mmol) andPdCl₂(dppf).CH₂Cl₂ (0.69 g, 0.84 mmol). The reaction was evacuated undervacuum and purged with N₂ 3×. The reaction was heated at 85° C. for 18 hand cooled to RT. The crude product was filtered through celite and wasrinsed with EtOAc followed by CH₂Cl₂. The crude filtrate wasconcentrated under vacuum and diluted in CH₂Cl₂ and water. The organiclayer was separated, and the remaining emulsion was acidified with 1 MHCl and extracted with EtOAc. The combined organic layers were washedwith water, brine, dried over MgSO₄, filtered, and concentrated. Thecrude product was purified by silica gel chromatography. The product waspartially concentrated to provide a precipitate which was filtered togive 3-(benzo[b]thiophen-2-yl)-6-chloropyridazine (2.36 g) as a lightyellow solid. The filtrate was recrystallized from CH₃CN to give3-(benzo[b]thiophen-2-yl)-6-chloropyridazine (0.46 g). LCMS Rt=1.57minutes (condition B); (M+1)=247.1.

Step 2:6-(benzo[b]thiophen-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine

To a suspension of 3-(benzo[b]thiophen-2-yl)-6-chloropyridazine (100 mg,0.41 mmol) in n-butanol (2 mL) in a 2 mL microwave vial was added1,2,2,6,6-pentamethylpiperidin-4-amine (276 mg, 1.62 mmol) and DIPEA(0.14 mL, 0.81 mmol). The reaction vessel was sealed and heated viamicrowave radiation for 180 min at 180° C. The crude reaction mixturewas diluted in EtOAc. The organic layer was washed with water (5×),brine, dried over MgSO₄, filtered and concentrated. The crude productwas purified via HPLC to give 25 mg of6-(benzo[b]thiophen-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine.LCMS Rt=0.54 min (LCMS method Q); (M+1)=381.1. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.73-7.82 (m, 1H), 7.64-7.73 (m, 1H), 7.54 (d, J=9.1Hz, 1H), 7.53 (s, 1H), 7.21-7.34 (m, 2H), 6.56 (d, J=9.3 Hz, 1H), 4.55(d, J=7.8 Hz, 1H), 4.14-4.32 (m, 1H), 2.20 (s, 3H), 1.93 (dd, J=12.4,3.8 Hz, 2H), 1.30 (apparent t, J=12.1 Hz, 2H), 1.07 (s, 6H), 1.10 (s,6H).

Example 8-1 Synthesis ofN-allyl-3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzamide

Step 1: 3-Methoxy-4-(6-(methyl(2,2,6,6tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzoic acid

To a microwave vial was added6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 100 mg, 0.35 mmol), 4-borono-3-methoxybenzoic acid(76 mg, 0.39 mmol), PdCl₂(dppf).CH₂Cl₂ (29 mg, 0.035 mmol), Na₂CO₃ (112mg, 1.06 mmol), DMF (2 mL) and water (0.5 mL). The microwave vial wassealed and heated in a microwave at 120° C. for 45 min. The crudereaction mixture was cooled and diluted in water and ether. The aqueouslayer was extracted with ether. The resultant emulsion was diluted inwater and 1 M NaOH. The aqueous layer was acidified with 1 M HCl slowlyand extracted again with ether. The organic layer was concentrated underreduced pressure, and the resulting precipitate was suspended in 10 mLMeOH and filtered. The filtrate was concentrated and used withoutfurther purification. LCMS Rt=0.63 min (condition B); MS (M+1)=399.0

Step 2: Synthesis ofN-allyl-3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzamide

To a solution of crude 3-methoxy-4-(6-(methyl(2,2,6,6tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzoic acid (0.354 mmol)in DMF (4 mL) and CH₂Cl₂ (4 mL) was added TEA (0.40 mL, 2.83 mmol),allyl amine (0.053 mL, 0.71 mmol), and HATU (202 mg, 0.53 mmol). Thecrude reaction was allowed to stir at RT overnight. The crude mixturewas quenched with sat aq NaHCO₃ and diluted with CH₂Cl₂. The organiclayer is washed with water (6×), brine, dried over MgSO₄, filtered, andconcentrated. The crude product was purified via HPLC to giveN-allyl-3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzamide(8.2 mg). LCMS Rt=1.08 min (condition B); MS (M+1)=438.1

Step 3

Following GENERAL METHOD 3-2 for methoxy deprotection using borontribromide,N-allyl-3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzamidewas prepared. NMR: ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.14 (d, J=10.10Hz, 1H), 7.85 (d, J=8.08 Hz, 1H), 7.42 (d, J=1.77 Hz, 1H), 7.39 (dd,J=8.21 Hz, 1.89 Hz, 1H), 7.31 (d, J=9.85 Hz, 1H), 5.95 (ddt, J=17.18 Hz,10.36 Hz, 5.43 Hz, 5.43 Hz, 1H), 5.25 (dq, J=17.18 Hz, 1.60 Hz, 1H),5.15 (dq, J=10.33 Hz, 1.44 Hz, 1H), 5.11 (br. s, 1H), 4.00 (dt, J=5.49Hz, 1.55 Hz, 2H), 3.02 (s, 3H), 1.65-1.74 (m, 2H), 1.52-1.63 (m, 2H),1.39 (s, 6H), 1.24 (s, 6H).

Example 9-1 Synthesis of2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

Step 1:6-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine

1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazolefrom Step 3 of Intermediate 2-1, was coupled with Intermediate 1-1 understandard Suzuki coupling methods as described in GENERAL METHOD 1-2 toprovide6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine.

Step 2:2-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

As described in GENERAL METHOD 3-1, thiophenol (0.127 mL, 1.24 mmol) wasadded to a microwave vial containing6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(520 mg, 1.24 mmol) and K₂CO₃ (171 mg, 1.24 mmol) in NMP (5 mL). Themicrowave vial was evacuated and filled with N₂ (2×). The reactionmixture was heated in the microwave at 190° C. for 30 min. The reactionmixture was filtered through celite (pre-packed filter funnel) washingwith MeOH. The filtrate was acidified to pH 3 using 1 M HCl aqueoussolution and then adsorbed onto a methanol conditioned SCX (10 g)column. The column was washed several times with methanol then elutedwith 2 N ammonia in methanol solution. The product was collected andconcentrated in vacuo to afford the crude product which was purified bypreparative HPLC under basic conditions to provide2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol(198 mg, MS: 407.25 [M+H⁺], LC/MS Rt=0.53 min (LCMS method Q); ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.86 (d, J=2.02 Hz, 1H), 7.71 (d, J=10.11Hz, 1H), 7.63 (d, J=1.52 Hz, 1H), 7.54 (d, J=8.59 Hz, 1H), 7.21-7.30 (m,2H), 6.91 (d, J=9.60 Hz, 1H) 6.31-6.41 (m, 1H), 4.76-4.95 (m, 1H),2.89-3.01 (m, 3H), 1.62 (dd, J=12.13, 3.54 Hz, 2H), 1.34 (br. s, 2H),1.27 (s, 6H), 1.10 (s, 6H).

Example 10-1 Synthesis of5-(5-methyl-oxazol-2-yl)-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol

Step 1:3-Methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-(prop-2-yn-1-yl)benzamide

To a crude solution of3-methoxy-4-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzoicacid (620 mg, 1.56 mmol) in DMF (10 mL) and CH₂Cl₂ (10 mL) was addedpropargyl amine (129 mg, 2.33 mmol), DIPEA (0.82 mL, 4.67 mmol) and HATU(887 mg, 2.33 mmol). The reaction was stirred at RT overnight, thendiluted with water and EtOAc. The layers were separated and the aqueouslayer was concentrated and partially dissolved in MeOH. The resultantwhite precipitate was filtered, and the MeOH filtrate was concentrated.The filtrate was dissolved in MeOH and the resultant precipitatefiltered. The filtrate was concentrated and purified via HPLC(C18sunfire column, 20% CH₃CN/H₂O to 100% CH₃CN, 0.1% NH₄OH aq. as modifierto give3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-(prop-2-yn-1-yl)benzamide(190 mg). LCMS Rt=0.86 min (condition B); MS (M+1)=436.3. ¹H NMR (400MHz, METHANOL-d₄) δ ppm 7.82 (d, J=9.6 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H),7.58 (d, J=1.5 Hz, 1H), 7.52 (dd, J=7.8, 1.5 Hz, 1H), 7.10 (d, J=9.6 Hz,1H), 5.15-5.27 (m, 1H), 4.18 (d, J=2.3 Hz, 2H), 3.93 (s, 3H), 2.99 (s,3H), 2.63 (t, J=2.5 Hz, 1H), 1.67 (dd, J=12.5, 3.4 Hz, 2H), 1.54 (t,J=12.5 Hz, 2H), 1.33 (s, 6H), 1.20 (s, 6H).

Step 2:6-(2-Methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine

To a solution of3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-(prop-2-yn-1-yl)benzamide(190 mg, 0.44 mmol) in dioxane (8 mL) was added 60% wt NaH (52 mg, 1.31mmol). The reaction was refluxed for 5 h, then cooled to RT and dilutedin EtOAc and water. The organic layer was washed with water, brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude material was purified via HPLC to give6-(2-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(106 mg). LCMS Rt=0.97 min (condition B); MS (M+1)=436.3. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.08 (d, J=8.1 Hz, 1H), 7.85 (d, J=9.6 Hz, 1H),7.72 (dd, J=8.1, 1.5 Hz, 1H), 7.65 (d, J=1.3 Hz, 1H), 6.88 (s, 1H), 6.82(d, J=9.6 Hz, 1H), 5.20-5.39 (m, 1H), 3.96 (s, 3H), 2.99 (s, 3H), 2.43(s, 3H), 1.74 (dd, J=12.4, 3.3 Hz, 2H), 1.47-1.59 (m, 2H), 1.43 (s, 6H),1.31 (s, 6H).

Step 3.5-(5-Methyl-oxazol-2-yl)-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol

To a solution of6-(2-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(106 mg, 0.24 mmol) in 2,4,6 collidine (8 mL, dried over MgSO₄, andfiltered), was added anhydrous LiI (292 mg, 2.18 mmol). The reaction wasstirred at 170° C. for 4 h, then cooled and diluted with small amountsof MeOH and EtOAc (150 mL) and H₂O (30 mL). The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified via HPLC to provide2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol(49 mg). LCMS Rt=0.55 min (LCMS method Q); MS (M+1)=422.3. ¹H NMR (400MHz, METHANOL-d4) δ ppm 8.12 (d, J=9.9 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H),7.53 (dd, J=6.1, 1.8 Hz, 1H), 7.51 (s, 1H), 7.30 (d, J=10.1 Hz, 1H),6.92 (d, J=1.0 Hz, 1H), 5.03-5.14 (m, 1H), 3.01 (s, 3H), 2.43 (d, J=1.2Hz, 3H), 1.68 (dd, J=12.6, 3.5 Hz, 2H), 1.56 (t, J=12.3 Hz, 2H), 1.37(s, 6H), 1.21 (s, 6H).

Example 11-1 Synthesis of5-(4-hydroxymethyl)-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Step 1. (1-(4-Bromo-3-methoxyphenyl)-1H-pyrazol-4-yl)methanol

A mixture of 4-(hydroxymethyl)pyrazole (500 mg, 5.10 mmol),salicylaldoxime (140 mg, 1.019 mmol), cesium carbonate (4.98 g, 15.29mmol), cuprous oxide (58.2 mg, 0.306 mmol), iodobromoanisole (1.59 g,5.10 mmol) and N,N-dimethyl-formamide (10 mL) were combined in amicrowave vial fitted with an N₂ inlet and magnetic stir bar. Thereaction mixture was stirred under a nitrogen atmosphere at 90° C.overnight. The reaction mixture was cooled to RT, then filtered throughcelite, and the filtrate was concentrated in vacuo. The crude materialwas purified by column chromotography (10% to 60% EtOAc in heptanes) togive (1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-4-yl)methanol (800 mg, MS:285.3 [M+H⁺].)

Step 2.(1-(3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-4-yl)methanol

To a microwave vial was added(1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-4-yl)methanol (400 mg, 1.41mmol), bis(pinacolato)diboron (538 mg, 2.12 mmol), potassium acetate(415 mg, 4.24 mmol), PdCl₂(dppf) (103 mg, 0.14 mmol), and dppf (78 mg,0.14 mmol), followed by addition of 1,4-dioxane (6 mL). The reactionmixture was purged with N₂ and stirred under an N₂ atmosphere at 90° C.overnight. The reaction mixture was filtered through a disposable filterfunnel and concentrated in vacuo. Purification by column chromotography(10% to 60% EtOAc in heptane) afforded(1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-4-yl)methanol(300 mg, MS: 331.2 [M+H+].).

Step 3.(1-(3-Methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1H-pyrazol-4-yl)methanol

To a microwave vial was added(1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-4-yl)methanol(87 mg, 0.26 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineIntermediate 1-1 (74.5 mg, 0.26 mmol), potassium phosphate (168 mg, 0.79mmol), Pd₂(dba)₃ (12.06 mg, 0.01 mmol), and SPhos (10.82 mg, 0.03 mmol),followed by addition of 1,4-dioxane (5 mL)/H₂O (1 mL). The vial waspurged with N₂ for 10 min and the reaction mixture was heated at 100° C.in the microwave for one hour. The reaction mixture was concentrated invacuo. The crude material was adjusted to pH 3 using 1 M HCl aqueoussolution and loaded on an SCX column. The crude material was washed withmethanol then eluted with 2 N ammonia in methanol. Theproduct-containing fractions were concentrated to afford(1-(3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1H-pyrazol-4-yl)methanol(100 mg, MS: 451.4 [M+H+].).

Step 45-(4-(Hydroxymethyl)-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Following standard GENERAL METHOD 3-1 for methoxy deprotection, thetitle compound was afforded as pale yellow powder (30 mg). MS: 437.2[M+H⁺], LCMS Rt=0.48 min (LCMS method Q); ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 7.88 (s, 1H), 7.73 (d, J=10.11 Hz, 1H), 7.65 (s, 1H), 7.55 (d,J=8.08 Hz, 1H), 7.20-7.27 (m, 2H), 6.93 (d, J=10.11 Hz, 1H), 4.86 (t,J=12.13 Hz, 1H), 4.61 (s, 2H), 2.91-2.98 (m, 3H), 1.62 (dd, J=12.38,3.28 Hz, 2H), 1.32-1.37 (m, 2H), 1.28 (s, 6H), 1.11 (s, 6H).

Example 12-1 Synthesis of5-(1H-imidazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethyl-piperidin-4-yl)amino)pyridazin-3-yl)phenol

Step 1. 1-(4-Bromo-3-methoxyphenyl)-1H-imidazole

A mixture of 2-(2-pyridyl)benzimidazole (287 mg, 1.469 mmol), cesiumcarbonate (5.98 g, 18.36 mmol), copper(I) iodide (280 mg, 1.469 mmol)and DMF (5 mL) were combined in a microwave vial fitted with an N₂ inletand magnetic stir bar. The slurry was heated at 60° C. for 1 h, followedby addition of imidazole (500 mg, 7.34 mmol) and1-bromo-4-iodo-2-methoxybenzene (2.3 g, 7.34 mmol). The reaction mixturewas heated at 90° C. for 2 days. The reaction mixture was filteredthrough celite, washed with EtOAc, and concentrated in vacuo. The crudematerial was purified by silica gel chromotography (10% to 40% EtOAc inheptanes) to give 1-(4-bromo-3-methoxyphenyl)-1H-imidazole (1.25 g, MS:255.2 [M+H⁺])

Step 2. (4-(1H-Imidazol-1-yl)-2-methoxyphenyl)boronic acid

To a stirred solution of 1-(4-bromo-3-methoxyphenyl)-1H-imidazole in THF(5 mL) was added 2.5 M n-butyl lithium in hexanes (0.348 ml, 0.869 mmol)dropwise at −78° C. over 15 min. After addition was complete, thereaction solution was stirred at −78° C. for 15 min, and trimethylborate (0.353 mL, 3.16 mmol) was added. The reaction was allowed to warmto RT, and continued to stir overnight. The reaction was quenched with 1M HCl aqueous solution to pH 2, diluted with water and extracted withDCM (3×). The product remained in the aqueous solution which wasconcentrated in vacuo to give crude(4-(1H-imidazol-1-yl)-2-methoxyphenyl)boronic acid (120 mg, MS: 219.2[M+H⁺]).

Step 3.6-(4-(1H-Imidazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a microwave vial was added(4-(1H-imidazol-1-yl)-2-methoxyphenyl)boronic acid (120 mg, 0.55 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineIntermediate 1-1 (156 mg, 0.55 mmol), potassium phosphate (351 mg, 1.65mmol), Pd₂(dba)₃ (25.2 mg, 0.028 mmol), and SPhos (22.6 mg, 0.05 mmol),followed by addition of 1,4-dioxane (2 mL)/H₂O (0.5 mL). The vial waspurged with N₂ for 10 minutes and the reaction mixture was heated at100° C. in the microwave for 40 min. The reaction mixture wasconcentrated in vacuo and adjusted to pH 3 by 1 M HCl aqueous solution,then loaded on an SCX column. The column was washed with methanol andeluted with 2 N NH₃ in methanol. The product-containing fractions wereconcentrated to afford6-(4-(1H-imidazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine(90 mg, MS: 421.4 [M+H⁺]).

Step 4:5-(1H-Imidazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethyl-piperidin-4-yl)amino)pyridazin-3-yl)phenol

Followed GENERAL METHOD 3-1 for methoxy deprotection using thiophenol,5-(1H-imidazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethyl-piperidin-4-yl)amino-)pyridazin-3-yl)phenolwas afforded as pale yellow powder (8 mg, MS: 407.2 [M+H+], LCMS Rt=0.40min (LCMS method Q); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.82 (br. s,1H), 7.70 (d, J=10.11 Hz, 1H), 7.55 (d, J=8.59 Hz, 1H), 7.23 (br. s,1H), 7.12 (br. s, 1H), 7.02 (d, J=2.02 Hz, 1H), 6.92 (d, J=10.11 Hz,1H), 6.85 (dd, J=8.59, 2.02 Hz, 1H), 4.86-4.92 (m, 1H), 2.94 (s, 3H),1.62 (dd, J=12.63, 3.54 Hz, 2H), 1.36 (br. s, 2H), 1.28 (s, 6H), 1.11(s, 6H).

Example 13-1 Synthesis of5-(4-amino-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Step 1: 1-(4-Bromo-3-methoxyphenyl)-1H-pyrazol-4-amine

A mixture of pyrazole-4-amine dihydrochloride (0.75 g, 4.79 mmol),salicylaldoxime (0.131 g, 0.96 mmol), cesium carbonate (4.69 g, 14.38mmol), cuprous oxide (0.06 g, 0.29 mmol),1-bromo-4-iodo-2-methoxybenzene (1.5 g, 4.79 mmol) andN,N-dimethyl-formamide (5 mL) were combined in a microwave vial fittedwith an N₂ inlet and magnetic stir bar. The reaction mixture was stirredunder a nitrogen atmosphere at 90° C. overnight. The solution obtainedwas allowed to cool to RT, then filtered through celite and the filtratewas concentrated in vacuo. The crude material was purified by silica gelchromotography (10% to 60% EtOAc in heptanes) to give1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-4-amine (250 mg, MS: 270.2[M+H⁺].)

Step 2:1-(3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-4-amine

To a microwave vial was added1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-4-amine (250 mg, 0.93 mmol),bis(pinacolato)diboron (355 mg, 1.39 mmol), potassium acetate (543 mg,5.59 mmol), PdCl₂(dppf) (68.20 mg, 0.09 mmol), and dppf (51.70 mg, 0.09mmol), followed by addition of 1,4-dioxane (2 mL). The reaction mixturewas purged with N₂ and stirred under N₂ protection at 90° C. overnight.The reaction mixture was filtered through a disposable filter funnel,concentrated in vacuo, and purified by column chromotography (10% to 60%EtOAc in heptane) to afford1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-4-amine(160 mg, MS: 316.2 [M+H⁺].).

Step 3:6-(4-(4-Amino-1H-pyrazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a microwave vial was added1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-4-amine(92 mg, 0.29 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineIntermediate 1-1 (75 mg, 0.27 mmol), potassium phosphate (169 mg, 0.78mmol), Pd₂(dba)₃ (12.14 mg, 0.01 mmol), and SPhos (10.89 mg, 0.03 mmol),followed by addition of 1,4-dioxane (1 mL)/H₂O (0.2 mL). The vial waspurged with N₂ for 10 minutes and the reaction mixture was heated at100° C. in a microwave reactor for one hour. The reaction mixture wasconcentrated in vacuo, then the crude material was adjusted to pH 3using 1 M HCl aqueous solution, then loaded on an SCX column. The columnwas washed with methanol then eluted with 2 N ammonia in methanol. Theproduct-containing fractions concentrated to afford6-(4-(4-amino-1H-pyrazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(100 mg, MS: 436.4 [M+H⁺].).

Step 4:5-(4-Amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

As described in GENERAL METHOD 3-1, thiophenol (0.02 mL, 0.23 mmol) wasadded to a microwave vial containing6-(4-(4-amino-1H-pyrazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(100 mg, 0.23 mmol) and K₂CO₃ (31.7 mg, 0.23 mmol) and NMP (2 mL). Themicrowave vial was evacuated and filled with N₂ (2×). The reactionmixture was heated in a microwave reactor at 190° C. for 20 min, thenfiltered through celite (pre-packed filter funnel) with methanol. Thefiltrate was acidified to pH 3 using 1 M HCl aqueous solution and thenadsorbed onto a methanol conditioned SCX column. The column was washedseveral times with methanol then eluted with 2 N ammonia in methanolsolution. The eluent was collected, concentrated in vacuo, then purifiedby preparative HPLC under basic conditions to give5-(4-amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(50 mg, MS: 422.26 [M+H⁺]; LCMS Rt=0.43 min (LCMS method Q); ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 7.68 (d, J=10.11 Hz, 1H), 7.49 (d, J=8.59 Hz,1H), 7.43 (s, 1H), 7.29 (s, 1H), 7.18 (dd, J=8.59, 2.53 Hz, 1H), 7.12(d, J=2.02 Hz, 1H), 6.89 (d, J=9.60 Hz, 1H), 4.77-4.93 (m, 1H), 2.92 (s,3H), 1.61 (dd, J=12.38, 3.28 Hz, 2H), 1.33 (t, J=12.38 Hz, 2H), 1.27 (s,6H), 1.10 (s, 6H).

Example 14-1 Synthesis of5-(4-amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Step 1: 3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

To a 25 mL microwave vial was added 4-bromo-3-methoxyphenol (1.0 g, 4.93mmol), bis(pinacolato)diboron (1.88 g, 7.39 mmol), potassium acetate(2.41 g, 24.63 mmol), PdCl₂(dppf) (0.36 g, 0.49 mmol), dppf (0.27 g,0.49 mmol), and 1,4-dioxane (10 mL). The reaction solution was purgedwith nitrogen (3×) and stirred at 90° C. overnight. The reaction mixturewas filtered through Celite and the filter cake was washed with EtOAC.The filtrate was concentrated in vacuo to give a brown liquid which waspurified by silica gel chromotography (10%-50% EtOAc/Heptane) to afford3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (700 mg,MS: 251.4 [M+H⁺].).

Step 2:3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

To a microwave vial was added3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(500 mg, 2.0 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineIntermediate 1-1 (565 mg, 2.0 mmol), potassium phosphate (1.27 g, 6.0mmol), Pd₂(dba)₃ (92 mg, 0.1 mmol), and SPhos (82 mg, 0.2 mmol),followed by addition of 1,4-dioxane (5 mL)/H₂O (1 mL). The vial waspurged with N₂ for 10 min and the reaction mixture was heated at 100° C.in a microwave reactor for one hour. The reaction mixture wasconcentrated in vacuo and the crude material was adjusted to pH 3 using1 M aqueous HCl, then loaded on an SCX column. The crude material waswashed with methanol then eluted with 2 N ammonia in methanol. Theproduct fractions were collected and dried to afford3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenolwhich was used without further purification.

Step 3:3-Methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate

To a solution of3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(120 mg, 0.32 mmol) in DCM (2 mL) was added triethylamine (0.113 mL,0.810 mmol) at RT. The reaction mixture was cooled to 0° C., followed byaddition of N-phenyltrifluoromethanesulfonimide (116 mg, 0.32 mmol). Thereaction mixture was warmed to RT and stirred for 2 h. The reaction wasquenched with aqueous sodium bicarbonate solution and extracted withDCM. The organic layer was dried over sodium sulfate, filtered andconcentrated to give the crude product which was adjusted to pH 3 using1 M HCl aqueous solution and loaded on an SCX column. The crude productwas washed with methanol then eluted with 2 N ammonia in methanol. Theproduct fractions were collected and dried to afford3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate (140 mg, MS: 503.4 [M+H⁺].).

Step 4:6-(2-Methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a microwave vial was added3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate (60 mg, 0.12 mmol), 1H-pyrazole-4-boronic acid(25.5 mg, 0.13 mmol), potassium phosphate (76 mg, 0.36 mmol), Pd₂(dba)₃(6 mg, 5.9 umol), and SPhos (5 mg, 0.012 mmol), followed by addition of1,4-dioxane (1 mL)/H₂O (0.2 mL). The vial was purged with N₂ for 10minutes and the reaction mixture was heated at 100° C. in the microwavefor one hour. The reaction mixture was concentrated in vacuo, and thecrude product was adjusted to pH 3 using 1 M aqueous HCl, then loaded onan SCX column. The crude product was washed with methanol then elutedwith 2 N ammonia in methanol. The product fractions were collected anddried to afford6-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(MS: 421.4 [M+H⁺].).

Step 5:2-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Following GENERAL METHOD 3-1 for methoxy deprotection using thiophenol,2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenolwas afforded as pale yellow powder (8 mg, MS: 407.2 [M+H⁺]; LCMS Rt=0.48min (LCMS method Q); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.83 (s, 2H),7.75 (d, J=10.11 Hz, 1H), 7.51 (d, J=8.08 Hz, 1H), 7.13-7.17 (m, 1H),7.01 (d, J=8.08 Hz, 1H), 6.93 (d, J=10.11 Hz, 1H), 4.85 (t, J=12.38 Hz,1H), 2.94 (s, 3H), 1.63 (dd, J=12.13, 3.03 Hz, 2H), 1.36 (t, J=12.38 Hz,2H), 1.29 (s, 6H), 1.13 (s, 6H).

Example 15-1 Synthesis of5-(3-amino-pyrazol-1-yl)-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol

Step 1: 1-(4-Bromo-3-methoxyphenyl)-3-nitro-1H-pyrazole

A mixture of 1-bromo-4-iodo-2-methoxybenzene (3.99 g, 12.75 mmol),3-nitro-1H-pyrazole (1.730 g, 15.30 mmol), Salicylaldoxime (0.350 g,2.55 mmol), Cu₂O (0.146 g, 1.020 mmol) and Cs₂CO₃ (6.23 g, 19.13 mmol)in DMF (13 mL) was degassed with N₂ and heated at 95° C. overnight.After cooling to RT, the mixture was filtered through celite and rinsedwith EtOAc. The filtrate was washed with water and brine. The organicsolution was dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was suspended in 5% MeOH/DCM, and the precipitate filtered,rinsed with 5% MeOH/DCM, and dried to give 2.3 g of1-(4-bromo-3-methoxyphenyl)-3-nitro-1H-pyrazole as a white solid. Thefiltrate from the above work up was purified by silica gelchromatography (EtOAc/Heptane=10:90 to 50:50) to give an additional 760mg of 1-(4-bromo-3-methoxyphenyl)-3-nitro-1H-pyrazole as a light yellowsolid.

Step 2: 1-(4-Bromo-3-methoxyphenyl)-1H-pyrazol-3-amine

To a mixture of 1-(4-bromo-3-methoxyphenyl)-3-nitro-1H-pyrazole (2.3 g,7.72 mmol) in DCM (24 mL) and acetic acid (6.18 mL, 108 mmol) was addedzinc dust (2.52 g, 38.6 mmol) at 0° C. The reaction mixture was stirredat 0° C. to RT overnight. The reaction mixture was filtered throughcelite, rinsed with EtOAc and concentrated in vacuo. The residue waspurified by silica chromotagraphy (EtOAc/heptane=10:90 to 50:50) to givea white foam which was dissolved in 6 mL of toluene, concentrated anddried to give 1.9 g of 1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-amine asa white powder.

Step 3.1-(3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-3-amine

A degassed reaction mixture of1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-amine (1 g, 3.73 mmol),bis(pinacolato) diboron (1.989 g, 7.83 mmol), Pd(dppf)Cl₂ (0.273 g,0.373 mmol), dppf (0.207 g, 0.373 mmol) and potassium acetate (2.56 g,26.1 mmol) in 1,4-dioxane (10 mL) was heated at 88° C. overnight. Aftercooling to RT, the mixture was filtered through celite and washed withEtOAc. The filtrate was concentrated and the residue was purified bysilica gel chromotagraphy (EtOAc/heptane=10:90 to 50:50, then 50:50 to60:40) to give 930 mg of1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-3-amineas a white solid.

Step 4.6-(4-(3-Amino-1H-pyrazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

A degassed reaction mixture of1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-3-amine(474 mg, 1.505 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineIntermediate 1-1 (370 mg, 1.308 mmol)tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.065 mmol) and 1 MNaHCO₃ (330 mg, 3.92 mmol) in 1,4-dioxane (7 mL) and water (2.3 mL) washeated at 100° C. for 14 h. After cooling to RT, the mixture wasfiltered through celite, washed with EtOAc, and the filtrate wasconcentrated. The residue was suspended in MeOH, acidified to pH 2-3using 1 M aqueous HCl and loaded on a 10 g SCX column. The column waswashed with MeOH, then eluted with 2 N NH₃ in MeOH. The collectedfractions were concentrated to give a light brown oil, which was treatedwith ether and concentrated to give 570 mg of6-(4-(3-amino-1H-pyrazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineas a light brown solid.

Step 5.5-(3-Amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

A degassed mixture of6-(4-(3-amino-1H-pyrazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(135 mg, 0.310 mmol), K₂CO₃ (42.8 mg, 0.310 mmol) and thiophenol (0.032mL, 0.310 mmol) in NMP (2 mL) was heated at 190° C. under microwaveradiation for 20 min. After addition of another 0.05 mmol of thiophenoland K₂CO₃, the mixture was heated at 190° C. under microwave radiationfor another 10 min. The mixture was acidified to pH 2-3 with 1 M HClaqueous solution, then loaded on a 5 g SCX column. The column was washedwith MeOH and eluted with 2 N NH₃ in MeOH. The collected fractions wereconcentrated and dissolved in a mixture of MeOH and DMSO, then purifiedby preparative HPLC to give 95 mg of5-(3-amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenolas a dark yellow solid. LCMS Rt=0.47 min (LCMS method Q), MS(M+1)=422.3, HRMS: 422.2672 [M+H⁺].

¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.08 (d, J=10.10 Hz, 1H), 7.98 (d,J=3.03 Hz, 1H), 7.80 (d, J=9.09 Hz, 1H), 7.31 (d, J=10.10 Hz, 1H),7.15-7.22 (m, 2H), 5.91 (d, J=2.53 Hz, 1H), 5.06 (m, 1H), 3.01 (s, 3H),1.70 (m, 2H), 1.51-1.65 (m, 2H), 1.39 (s, 6H), 1.24 (s, 6H).

The following final compounds were prepared using similar procedures asin Examples 9-1 through 15-1, and general methods as outlined in theGENERAL METHODS section.

LCMS M + 1, Rt, Example Compound conditions ¹H NMR 400 MHz 16-1

520.6 0.43 min Q CHLOROFORM-d δ 13.75 (s, 1H), 7.71-7.80 (m, 2H), 7.68(s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.89-7.01(m, 2H), 5.00 (m, 1H), 4.20 (t, J = 6.6 Hz, 2H), 3.58-3.69 (m, 4H), 2.93(s, 3H), 2.77 (t, J = 6.6 Hz, 2H), 2.39-2.48 (m, 4H), 1.65 (dd, J =12.4, 3.3 Hz, 2H), 1.51 (br. s., 2H), 1.36 (br. s, 6H), 1.18-1.31 (m,6H) 16-2

421.4 0.51 min Q CHLOROFORM-d d 13.75 (br. s., 1H), 7.70-7.77 (m, 2H),7.56 (s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.06-7.12 (m, 1H), 6.89-7.00 (m,2H), 4.82 (t, J = 12.4 Hz, 1H), 3.87 (s, 3H), 2.91-2.98 (m, 3H), 1.63(dd, J = 12.4, 3.3 Hz, 2H), 1.34 (t, J = 12.4 Hz, 2H), 1.28 (s, 6H),1.09-1.14 (m, 6H) 16-3

422.3 0.43 min Q METHANOL-d4 δ 8.08 (d, J = 10.11 Hz, 1H), 7.87 (d, J =8.59 Hz, 1H), 7.36 (d, J = 2.02 Hz, 1 H), 7.29 (d, J = 9.60 Hz, 1H),7.06-7.21 (m, 2H), 7.06-7.21 (m, 2H), 5.62 (d, J = 2.02 Hz, 1H),4.97-5.19 (m, 1H), 3.02 (s, 3H), 1.70 (dd, J = 12.63, 3.54 Hz, 2H), 1.56(t, J = 12.13 Hz, 2H), 1.38 (s, 6H), 1.22 (s, 6H) 16-4

407.2 0.51 min Q CHLOROFORM-d δ 8.69 (d, J = 11.8 Hz, 1H), 8.51 (d, J =2.0 Hz, 1H), 8.41 (d, J = 9.8 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H),7.65-7.80 (m, 3H), 7.52 (d, J = 9.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H),6.48-6.59 (m, 1H), 5.09-5.22 (m, 1H), 3.01 (s, 3H), 1.79-1.98 (m, 4H),1.53 (s, 6H), 1.42 (s, 6H) 16-5

437.4 0.51 min Q METHANOL-d4 δ 7.99 (s, 1H), 7.91 (d, J = 9.6 Hz, 1H),7.70 (d, J = 8.6 Hz, 1H), 7.63 (s, 1H), 7.20-7.29 (m, 3H), 6.40-6.44 (m,1H), 5.08-5.24 (m, 1H), 3.66 (t, J = 6.1 Hz, 2H), 3.47-3.56 (m, 2H),2.13 (t, J = 12.9 Hz, 2H), 1.82-1.94 (m, 2H), 1.56 (s, 6H), 1.48 (s, 6H)

Example 17-1 Synthesis of2-(6-(piperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

Step 1. tert-Butyl4-((6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)oxy)-piperidine-1-carboxylate

Potassium tert-butoxide (1.0 M in THF, 0.82 mL, 0.82 mmol) was added totert-butyl 4-hydroxypiperidine-1-carboxylate (0.17 g, 0.82 mmol) in THF(3 mL) at 0° C. and the mixture was stirred for 10 min at 0° C.3-Chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine Intermediate2-1 (0.13 g, 0.45 mmol) was added to the reaction at 0° C. and themixture was stirred for 1 h at RT. After evaporation under reducedpressure, the crude material was purified by silica chromatography (70to 100% EtOAc in heptane) to give tert-butyl4-((6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)oxy)piperidine-1-carboxylate(0.18 g, 89%) as a colorless solid.

Step 2:3-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(piperidin-4-yloxy)pyridazine

Trifluoroacetic acid (1 mL) was added to tert-butyl4-((6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)oxy)piperidine-1-carboxylate(0.18 g, 0.40 mmol) in DCM (3 mL) at 0° C. The reaction was stirred for1 h at RT. The reaction mixture was added to an aqueous solution of NaOH(1 M) and the aqueous phase was extracted with chloroform/propan-2-ol(3:1). The combined organic phases were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(piperidin-4-yloxy)pyridazine(0.14 g, 100%) as a colorless solid.

Step 3:2-(6-(Piperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

Following GENERAL METHOD 3-1 for methoxy deprotection with thiophenol,3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(piperidin-4-yloxy)pyridazine(70 mg, 0.20 mmol) was treated with thiophenol (27 mg, 0.24 mmol) andK₂CO₃ (25 mg, 0.18 mmol) in NMP (1.3 mL) for 15 min at 190° C. HPLCpurification (0.1% trifluoroacetic acid as modifier) afforded2-(6-(piperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol (12mg, 18%) as a yellow solid. LCMS Rt=0.50 min (LCMS method Q); [M+H]:338.16; ¹H NMR (400 MHz, DMSO-d6) δ 13.01 (bs, 1H), 8.53 (d, J=2.5 Hz,1H), 8.46 (bs, 2H), 8.45 (d, J=9.5 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.47(dd, J=8.5, 2.5 Hz, 2H), 7.44 (d, J=9.5 Hz, 1H), 6.51-6.62 (m, 1H), 5.51(tt, J=7.5, 3.5 Hz, 1H), 3.33 (br. s, 2H), 3.20 (br. s, 2H), 2.18-2.31(m, 2H), 2.01 (ddt, J=13.5, 8.5, 4.0 Hz, 2H).

Example 17-2 Synthesis of2-(6-M2S,4R,6R)-2,6-Dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

Step 1:3-(((2S,4R,6R)-2,6-Dimethylpiperidin-4-yl)oxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine

Potassium tert-butoxide (1.0 M in THF, 0.72 mL, 0.72 mmol) was added to2,6-dimethylpiperidin-4-ol (0.09 g, 0.66 mmol) in THF (3 mL) at 0° C.and the mixture was stirred for 10 min at 0° C.3-Chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine Intermediate2-1 (0.15 g, 0.51 mmol) was added to the reaction at 0° C. and themixture was stirred for 1 h at RT. Water was added and the aqueous phasewas extracted with chloroform/propan-2-ol (3:1). The combined organicphases were dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude material was purified by silicachromatography (silica gel saturated with Et₃N, 1 to 15% MeOH in DCM) togive3-(((2S,4R,6R)-2,6-dimethylpiperidin-4-yl)oxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine(59 mg, 31%) as a colorless solid. A racemic mixture of3-(((2R,6R)-2,6-dimethylpiperidin-4-yl)oxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazineand3-(((2S,6S)-2,6-dimethylpiperidin-4-yl)oxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine(91 mg, 47%) was also isolated as a colorless solid (intermediates forExample 17-3, 17-4 below).

Step 2:2-(6-(((2S,4R,6R)-2,6-Dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

Following the GENERAL METHOD 3-1 for deprotection with thiophenol,3-(((2S,4r,6R)-2,6-dimethylpiperidin-4-yl)oxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine(55 mg, 0.15 mmol) was treated with thiophenol (0.11 M in NMP, 1.5 mL,0.17 mmol) and K₂CO₃ (18 mg, 0.13 mmol) in NMP (1.5 mL) for 15 min at190° C. After HPLC purification (0.1% trifluoroacetic acid as modifier),the product-containing fractions were free based by catch and releaseusing SiliaBond Propylsulfonic Acid® (2 g, MeOH as eluent and a 2 Nammonia solution in MeOH to release the material). Evaporation underreduced pressure afforded2-(6-(((2S,4R,6R)-2,6-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol(9 mg, 17%) as a yellow solid. LCMS Rt=0.50 min (LCMS method Q); [M+H]:366.191; ¹H NMR (400 MHz, DMSO-d6) δ 8.66 (bs, 1H), 8.53 (d, J=2.5 Hz,1H), 8.45 (d, J=9.5 Hz, 1H), 8.12 (bs, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.77(d, J=2.0 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.47 (dd, J=8.5, 2.0 Hz, 1H),7.43 (d, J=9.5 Hz, 1H), 6.56 (dd, J=2.5, 2.0 Hz, 1H), 5-38-5.60 (m, 1H),3.47 (bs, 2H), 2.45 (bs, 2H), 1.59 (q, J=12.0 Hz, 2H), 1.32 (d, J=6.5Hz, 6H).

Example 17-3 and 17-4 Synthesis of2-(6-((-2,6-Dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol,Enantiomer 1 and Enantiomer 2

The racemic mixture isolated from Step 1 of Example 17-2 was deprotectedfollowing GENERAL METHOD 3-1. The racemate (91 mg, 0.24 mmol) wastreated with thiophenol (30 mg, 0.27 mmol) and K₂CO₃ (30 mg, 0.22 mmol)in NMP (1.6 mL) for 15 min at 190° C. After preparative HPLCpurification (0.1% trifluoroacetic acid as modifier), the desiredfractions were free based by catch and release using SiliaBondPropylsulfonic Acid® (2 g, MeOH as eluent and a 2 N ammonia solution inMeOH to release the material). Enantiomers 1 and Enantiomer 2 wereisolated via normal phase preparative HPLC (AD-H 4.6×250 mm column, 40%EtOH (diethylamine as modifier) in heptane). Two solids (5 mg (6%) and 3mg (3%)) were afforded. LCMS Rt=0.50 min (LCMS method Q); [M+H]: 366.21;¹H NMR (400 MHz, DMSO-d6) δ 13.16 (bs, 1H), 8.52 (d, J=2.5 Hz, 1H), 8.40(d, J=9.5 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.47(d, J=2.5 Hz, 1H), 7.45 (dd, J=8.5, 2.5 Hz, 1H), 7.35 (d, J=9.5 Hz, 1H),6.54 (dd, J=2.5, 1.5 Hz, 1H), 5.52 (td, J=10.0, 5.0 Hz, 1H), 3.29-3.45(m, 1H), 3.07 (dqd, J=9.5, 6.5, 3.0 Hz, 1H), 2.09-2.22 (m, 1H),1.86-1.97 (m, 1H), 1.67 (ddd, J=12.0, 10.0, 5.0 Hz, 1H), 1.20-1.28 (m,1H), 1.18 (d, J=7.0 Hz, 3H), 1.05 (d, J=6.5 Hz, 3H).

Example 17-5 Synthesis of5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-yloxy)pyridazin-3-yl)phenol

Step 1. tert-Butyl3-((6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)oxy)-pyrrolidine-1-carboxylate

Potassium tert-butoxide (1.0 M in THF, 0.98 mL, 0.98 mmol) was added totert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.18 g, 0.98 mmol) in THF(3.3 mL) at 0° C. and the mixture was stirred for 10 min at 50° C.3-Chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine Intermediate2-1 (0.12 g, 0.40 mmol) was added to the reaction at 0° C. and themixture was stirred for 2 h at RT. Water (0.1 mL) was added and thesolvent was concentrated under reduced pressure to afford (0.18 g, 100%)of a brown solid.

Step 2:3-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(pyrrolidin-3-yloxy)pyridazine

Trifluoroacetic acid (1 mL) was added to tert-butyl3-((6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)oxy)pyrrolidine-1-carboxylate(0.18 g, 0.40 mmol) in DCM (3 mL) at 0° C. The reaction was stirred for2 days at RT. The reaction mixture was added to an aqueous solution ofNaOH (1 M) and the aqueous phase was extracted withchloroform/propan-2-ol (3:1). The combined organic phases were driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto afford3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(pyrrolidin-3-yloxy)pyridazine(0.14 g, 100%) as a brown solid.

Step 3:5-(1H-Pyrazol-1-yl)-2-(6-(pyrrolidin-3-yloxy)pyridazin-3-yl)phenol

Following GENERAL METHOD 3-1 for phenol deprotection using thiophenol,3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(pyrrolidin-3-yloxy)pyridazine(91 mg, 0.24 mmol) was treated with thiophenol (30 mg, 0.27 mmol) andK₂CO₃ (30 mg, 0.22 mmol) in NMP (1.6 mL) for 15 min at 190° C. AfterHPLC purification (0.1% trifluoroacetic acid as modifier), theproduct-containing fractions were free based by catch and release usingSiliaBond Propylsulfonic Acid® (2 g, MeOH as eluent and a 2 N ammoniasolution in MeOH to release the material). Solvent was concentratedunder reduced pressure and a pale brown solid (83 mg, 68%) was afforded.LCMS Rt=0.48 min (LCMS method Q); [M+H]: 324.1457; ¹H NMR (400 MHz,CHLOROFORM-d) δ 13.62 (bs, 1H), 7.97 (d, J=2.5 Hz, 1H), 7.97 (d, J=9.5Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.39-7.43 (m,1H), 7.38 (d, J=2.5 Hz, 1H), 7.12 (d, J=9.5 Hz, 1H), 6.44-6.51 (m, 1H),5.74 (ddt, J=7.0, 5.0, 2.5 Hz, 1H), 3.24-3.31 (m, 2H), 3.17-3.24 (m,1H), 3.02 (ddd, J=11.0, 8.5, 5.5 Hz, 1H), 2.20-2.33 (m, 1H), 2.02-2.11(m, 1H).

Example 17-6 and 17-7 Synthesis of2-(6-(((2S,4S)-2-Methylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol,Enantiomer 1 and Enantiomer 2

Potassium tert-butoxide (1.0 M in THF, 1.4 mL, 1.4 mmol) was added tocis-2-methylpiperidin-4-ol (0.10 g, 0.68 mmol) in THF (3 mL) and themixture was stirred for 10 min at 50° C.2-(6-Chloropyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol Intermediate 2-2(0.08 g, 0.28 mmol) was added to the reaction at 0° C. and the mixturewas stirred for 2 days at RT. Trifluoroacetic acid (0.3 mL) was addedand the solvent was evaporated under reduced pressure. The crudematerial was purified via preparative HPLC (5 to 95% acetonitrile inwater, 0.1% trifluoroacetic acid as modifier). Enantiomer 1 andEnantiomer 2 were isolated via preparative SFC. Two solids (10 mg (10%)and (15 mg (16%)) were afforded.

Example 17-6, Enantiomer 1

LCMS Rt=0.48 min (LCMS method Q); [M+H]: 352.1; ¹H NMR (400 MHz,METHANOL-d4) δ 8.28 (d, J=9.5 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H), 7.93 (d,J=8.5 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.37 (dd,J=8.5, 2.5 Hz, 1H), 7.26 (d, J=9.5 Hz, 1H), 6.50-6.56 (m, 1H), 5.31 (tt,J=11.0, 4.5 Hz, 1H), 3.20 (ddd, J=13.0, 4.5, 2.5 Hz, 1H), 2.90-2.97 (m,1H), 2.84 (td, J=13.0, 2.5 Hz, 2H), 2.31 (dddq, J=17.0, 12.0, 4.5, 2.5zHz, 2H), 1.63 (tdd, J=13.0, 11.0, 4.5 Hz, 1H), 1.32-1.38 (m, 1H), 1.20(d, J=6.5 Hz, 3H)

Example 17-7, Enantiomer 2

LCMS Rt=0.48 min (LCMS method Q); [M+H]: 352.1; ¹H NMR (400 MHz,DMSO-d6) δ 13.2 (bs, 1H), 8.52 (d, J=2.5 Hz, 1H), 8.40 (d, J=9.5 Hz,1H), 8.03 (d, J=8.5 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.48 (d, J=2.0 Hz,1H), 7.45 (dd, J=8.5, 2.0 Hz, 1H), 7.37 (d, J=9.5 Hz, 1H), 6.51-6.59 (m,1H), 5.24 (tt, J=11.0, 4.5 Hz, 1H), 3.06 (ddd, J=12.0, 4.5, 2.5 Hz, 1H),2.70-2.81 (m, 1H), 2.62-2.71 (m, 1H), 2.09-2.23 (m, 2H), 1.47 (qd,J=12.0, 4.5 Hz, 1H), 1.13-1.21 (m, 1H), 1.07 (d, J=6.0 Hz, 3H).

Example 17-8 and 17-9 Synthesis of(5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-ylmethoxy)pyridazin-3-yl)phenol,Enantiomer 1 and Enantiomer

Potassium tert-butoxide (1.0 M in THF, 0.7 mL, 0.7 mmol) was added topyrrolidin-3-ylmethanol (0.06 g, 0.64 mmol) in THF (1.4 mL) and themixture was stirred for 10 min at 50° C.2-(6-Chloropyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol Intermediate 2-2(0.05 g, 0.18 mmol) was added to the reaction at 0° C. and the mixturewas stirred for 1 h at RT. Solvent was evaporated under reducedpressure. The crude material was purified via reverse phase preparativeHPLC (5 to 95% acetonitrile in water, 5 mM NH₄OH as modifier).Enantiomer 1 and Enantiomer 2 were isolated via preparative SFC. Twosolids (11 mg (17%), and 12 mg (20%) were afforded.

Example 17-8, Enantiomer 1

LCMS Rt=0.48 min (LCMS method Q); [M+H]: 338.161; ¹H NMR (400 MHz,METHANOL-d4) δ 8.31 (d, J=9.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 7.94 (d,J=8.5 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.38 (dd,J=8.5, 2.0 Hz, 1H), 7.34 (d, J=9.5 Hz, 1H), 6.51-6.56 (m, 1H), 4.55-4.66(m, 2H), 3.39-3.43 (m, 1H), 3.21-3.28 (m, 1H), 3.10-3.19 (m, 1H), 3.04(dd, J=11.5, 7.0 Hz, 1H), 2.86 (hept, J=7.0 Hz, 1H), 2.20 (dtd, J=13.5,8.1, 5.5 Hz, 1H), 1.84 (dq, J=13.5, 7.5 Hz, 1H).

Example 17-9, Enantiomer 2

LCMS Rt=0.47 min (LCMS method Q); [M+H]: 338.161; ¹H NMR (400 MHz,DMSO-d6) δ 13.0 (bs, 1H), 8.52 (d, J=2.5 Hz, 1H), 8.44 (d, J=9.5 Hz,1H), 8.04 (d, J=8.5 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.49 (d, J=2.0 Hz,1H), 7.46 (dd, J=8.5, 2.0 Hz, 1H), 7.45 (d, J=9.5 Hz, 1H), 6.52-6.59 (m,1H), 4.42-4.60 (m, 2H), 3.36 (dd, J=11.5, 8.0 Hz, 1H), 3.22-3.32 (m,1H), 3.16 (m, 1H), 3.07 (dd, J=11.5, 7.0 Hz, 1H), 2.84 (pentet, J=7.5Hz, 1H), 2.14 (dtd, J=13.0, 7.5, 5.5 Hz, 1H), 1.81 (dq, J=13.0, 7.5 Hz,1H).

The following final compounds were prepared using similar procedures asin Examples 17-1 to 17-9, and general methods as outlined in the GENERALMETHODS section when appropriate.

LCMS M + 1, Rt, Example Compound conditions ¹H NMR 400 MHz 17-10

356.1 0.46 min Q METHANOL-d4 δ 8.07-8.14 (m, 1H), 8.00 (d, J = 2.3 Hz,1H), 7.73- 7.80 (m, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.42 (s, 1H), 7.26(dq, J = 4.6, 2.3 Hz, 2H), 7.22 (d, J = 9.3 Hz, 1H), 6.41-6.48 (m, 1H),5.31-5.46 (m, 1H), 4.85-5.09 (m, 1H), 3.27- 3.35 (m, 1H), 3.10 (d, J =14.8 Hz, 1H), 2.79-2.96 (m, 1H), 2.66-2.78 (m, 1H), 1.97-2.07 (m, 2H)17-11

408.3 0.51 min Q CHLOROFORM-d δ 13.69 (br. s, 1H), 7.80-7.90 (m, 2H),7.63 (d, J = 1.5 Hz, 1H), 7.57-7.62 (m, 1H), 7.25-7.31 (m, 2H), 6.97 (d,J = 9.6 Hz, 1H), 6.38 (t, J = 2.3 Hz, 1H), 5.53 (tt, J = 11.3, 4.1 Hz,1H), 2.21 (s, 3H), 2.05 (dd, J = 11.9, 3.8 Hz, 2H), 1.56 (t, J = 11.6Hz, 2H), 1.10 (s, 6H), 1.13 (s, 6H) 17-12

394.2 0.61 min Q METHANOL-d4 δ ppm 8.20-8.32 (m, 2H), 7.92 (d, J = 8.59Hz, 1H), 7.73 (d, J = 1.52 Hz, 1H), 7.39-7.40 (m, 1H), 7.34-7.39 (m,1H), 7.24 (d, J = 9.60 Hz, 1H), 6.51-6.55 (m, 1H), 5.70-5.80 (m, 1H),2.21 (dd, J = 12.88, 4.29 Hz, 2H), 1.42 (t, J = 11.62 Hz, 2H), 1.33-1.37(s, 6H), 1.23 (s, 6H)

Example 17-13 Synthesis of5-(1H-Pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolhydrochloride salt

Step 1:3-(4-Chloro-2-methoxyphenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine

A mixture of 4-chloro-2-methoxyphenylboronic acid (1.12 g, 6.00 mmol),Intermediate 1-3 (1.94 g, 7.20 mmol), SiliaCat® DPP-Pd (1.15 g, 0.30mmol) and potassium carbonate in ethanol/water (10:1, 33 mL) was heatedat reflux for 5 h. The solvent was evaporated and the resulting brownresidue was partitioned between DCM and an 8% aqueous solution of K₂CO₃.After separation, the aqueous layer was extracted with DCM. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to dryness in vacuo. The crude material was purified byflash chromatography (30 uM amine, —(CH₂)₃NH₂, functionalized silicagel, 30 to 100% Et₂O in heptane) to give a mixture (1.76 g) of thedesired product (75%) and Intermediate 1-3 (25%). [M+H]: 376.3; ¹H NMR(400 MHz, DMSO-d6) δ 7.91 (d, J=9.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H),7.27 (d, J=2.0 Hz, 1H), 7.12-7.20 (m, 2H), 5.68 (tt, J=11.0, 4.0 Hz,1H), 3.85 (s, 3H), 1.99-2.11 (m, 2H), 1.20-1.30 (m, 8H), 1.10 (s, 6H).

Step 2:3-(2-Methoxy-4-(1H-pyrazol-4-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine

SiliaCat® DPP-Pd (0.37 g, 0.10 mmol) was added to a microwave vialcontaining a mixture of3-(4-chloro-2-methoxyphenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine(0.36 g, 0.96 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.47 g, 2.4mmol), and K₂CO₃ (0.53 g, 3.8 mmol) in ethanol/water (10:1, 6.6 mL). Thereaction mixture was sealed, then heated in a microwave reactor at 160°C. for 1 h. After cooling, the reaction was purified by solid phaseextraction (5 g SiliaBond Carbonate®, MeOH as eluent). The filtrate wasconcentrated in vacuo and the resulting residue was purified by flashchromatography (silica gel saturated with Et₃N, 2 to 25% MeOH in DCM) togive the desired product (0.08 mg, 21%). [M+H]: 408.4; ¹H NMR (400 MHz,DMSO-d6) δ 13.01 (bs, 1H), 8.33 (bs, 1H), 8.05 (bs, 1H), 7.94 (d, J=9.5Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.38 (d, J=1.5 Hz, 1H), 7.34 (dd,J=8.0, 1.5 Hz, 1H), 7.14 (d, J=9.5 Hz, 1H), 5.57-5.74 (m, 1H), 3.90 (s,3H), 2.00-2.14 (m, 2H), 1.17-1.31 (m, 8H), 1.11 (s, 6H).

Step 3:5-(1H-Pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol.Hydrochloride salt

Following GENERAL METHOD 3-1 for phenol deprotection using thiophenol,3-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine(0.58 mg, 1.41 mmol) was treated with thiophenol (0.15 mg, 1.36 mmol)and K₂CO₃ (0.23 mg, 1.64 mmol) in NMP (9 mL) for 15 min at 190° C. Afterpurification (0.1% trifluoroacetic acid as modifier), desired fractionswere free based by catch and release using SiliaBond PropylsulfonicAcid® (5 g, MeOH as eluent and a 2 N ammonia solution in MeOH to releasethe material). The solvent was evaporated under reduced pressure. Theresulting beige solid was dissolved in CH₃CN/H₂O/MeOH (6/1/6 mL) andSiliaMetS® DMT (2.7 g, 1.4 mmol) was added and the mixture was shaken 18h. The mixture was then filtered through a small celite plug and thefiltrate was purified by catch and release using SiliaBondPropylsulfonic Acid® (5 g, MeOH as eluent and a 2 N ammonia solution inMeOH to release the material). The solvent was concentrated in vacuo andthe resulting solid was suspended in CH₃CN/H₂O (4/1 mL). 4 N HCl in1,4-dioxane (4 equivalents) was added and solvent was concentrated invacuo to afford a yellow solid (59 mg, 9%). LCMS RT=0.51 min (LCMSmethod Q); [M+H]: 394.2225; ¹H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=12.0Hz, 1H), 8.49 (d, J=9.5 Hz, 1H), 8.36 (d, J=12.0 Hz, 1H), 8.16 (s, 1H),7.94 (d, J=8.0 Hz, 1H), 7.47 (d, J=9.5 Hz, 1H), 7.21-7.28 (m, 2H),5.63-5.87 (m, 1H), 2.34 (dd, J=13.0, 4.0 Hz, 2H), 1.81 (dd, J=13.0, 10.5Hz, 2H), 1.53 (s, 6H), 1.50 (s, 6H).

Example 18-1 Synthesis of2-(6-piperazin-1-yl-pyridazin-3-yl)-5-pyrazol-1-yl-phenol HCl salt

Step 1 (N-arylation): tert-Butyl4-(6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)piperazine-1-carboxylate

Following GENERAL METHOD 6-1 for S_(N)Ar, Intermediate 2-1 (50 mg, 0.174mmol), tert-butyl piperazine-1-carboxylate (59 mg, 0.314 mmol), DIPEA(0.06 mL, 0.349 mmol), and n-butanol (0.1 mL) were combined in a 4 mLreaction vial and heated at 120° C. overnight. The reaction was cooledto RT and EtOAc was added. The white solid that formed was filtered offand washed with EtOAc, dissolved in DCM and washed with H₂O. The organiclayer was dried with sodium sulfate, filtered, and concentrated in vacuoto afford the desired product.

Step 2

tert-Butyl4-(6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)piperazine-1-carboxylate(49.2 mg, 0.11 mmol), K₂CO₃ (15.6 mg, 0.11 mmol), thiophenol (17.2 uL,0.17 mmol), and NMP (0.23 mL) were combined in a 2 mL microwave vial andheated in the microwave at 190° C. for 0.5 hrs. The reaction mixture wascooled to RT and acidified with 5% aq. citric acid. EtOAc was added andthe resulting product precipitate was isolated by filtration.

Step 3

The Step 2 precipitate was dissolved in 4 M HCl in 1,4-dioxane (2 mL)and stirred at RT for 0.5 hrs then concentrated to provide2-(6-(piperazin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol, (11.0mg, 0.03 mmol, 30% yield). LCMS Rt=0.46 min, M+1=323.5 (LCMS method Q).¹H NMR (DMSO-d6) δ 9.32 (br. s, 2H), 8.60 (d, J=2.3 Hz, 1H), 8.40 (d,J=10.0 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.71-7.85 (m, 2H), 7.43-7.56 (m,2H), 6.54-6.63 (m, 1H), 3.86-4.02 (m, 4H), 3.41-3.78 (m, 2H), 2.60-2.83(m, 2H).

The following compounds were prepared using similar procedures as inExample 18-1:

LCMS M + 1, Rt, Example Compound conditions ¹H NMR 400 MHz 18-2

293.2 0.37 min Q DMSO-d6 δ 8.47 (s, 1H), 8.32 (d, J = 9.6 Hz, 1H),7.85-7.90 (m, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.27-7.48 (m, 4H), 7.12 (d,J = 9.6 Hz, 1H), 4.75 (quintd, J = 6.9 Hz, 1H), 3.81 (dd, J = 8.6, 7.6Hz, 2H), 3.53 (dd, J = 8.3, 7.1 Hz, 2H) 18-3

309.1 0.44 min Q DMSO-d6 δ 8.59 (d, J = 2.5 Hz, 1H), 8.18 (d, J = 9.5Hz, 1H), 7.95 (d, J = 9.3 Hz, 1H), 7.69-7.84 (m, 2H), 7.39-7.48 (m, 2H),7.09 (d, J = 9.8 Hz, 1H), 6.56 (dd, J = 2.5, 1.8 Hz, 1H), 4.71 (quint, J= 6.9 Hz, 1H), 3.67-3.82 (m, 2H), 3.43-3.54 (m, 2H) 18-4

351.2 0.48 min Q DMSO-d6 δ 14.11 (br. s, 1H), 8.60 (d, J = 2.0 Hz, 1H),8.26 (d, J = 10.0 Hz, 1H), 7.95-8.09 (m, 1H), 7.77 (d, J = 1.5 Hz, 1H),7.58 (d, J = 10.0 Hz, 1H), 7.41-7.48 (m, 2H), 6.56 (dd, J = 2.5, 1.8 Hz,1H), 4.30 (dd, J = 12.4, 1.9 Hz, 2H), 2.72-2.86 (m, 2H), 2.42 (dd, J =12.4, 10.7 Hz, 2H), 1.05 (d, J = 6.3 Hz, 6H) 18-5

377.1 0.42 min Q DMSO-d6 δ 8.59 (d, J = 2.3 Hz, 1H), 8.24 (d, J = 9.8Hz, 1H), 7.95-8.05 (m, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.38-7.48 (m, 2H),7.18 (d, J = 9.8 Hz, 1H), 6.56 (dd, J = 2.5, 1.8 Hz, 1H), 3.37-3.72 (m,4H), 2.53-2.66 (m, 2H), 2.35-2.49 (m, 2H), 2.25 (s, 3H), 1.92-2.10 (m,2H), 1.72-1.86 (m, 2H) 18-6

337.2 0.46 min Q METHANOL-d4 δ 7.91 (d, J = 2.5 Hz, 1H), 7.80 (d, J =9.6 Hz, 1H), 7.57- 7.65 (m, 2H), 7.22 (dq, J = 4.4, 2.4 Hz, 2H), 7.03(d, J = 10.1 Hz, 1H), 6.40 (t, J = 2.0 Hz, 1H), 3.81-3.89 (m, 2H), 3.74(t, J = 6.1 Hz, 2H), 3.04- 3.13 (m, 2H), 2.87-2.95 (m, 2H), 1.93-2.03(m, 2H) 18-7

367.1 0.44 min Q DMSO-d6 δ 14.05 (s, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.29(d, J = 10.0 Hz, 1H), 8.03 (d, J = 9.3 Hz, 1H), 7.73- 7.80 (m, 1H), 7.59(d, J = 10.0 Hz, 1H), 7.38-7.50 (m, 2H), 6.53-6.60 (m, 1H), 4.49 (t, J =5.3 Hz, 1H), 3.60- 3.72 (m, 4H), 3.55 (q, J = 6.0 Hz, 2H), 2.53-2.60 (m,4H), 2.45 (t, J = 6.1 Hz, 2H) 18-8

349.1 0.46 min Q METHANOL-d4 δ 8.21 (d, J = 2.5 Hz, 1H), 8.07 (d, J =9.6 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 1.5 Hz, 1H),7.28-7.39 (m, 3H), 6.52 (t, J = 2.3 Hz, 1H), 4.13 (dd, J = 11.9, 2.8 Hz,1H), 4.04 (dd, J = 12.4, 2.8 Hz, 1H), 3.66 (br. s, 1H), 3.22 (d, J =11.6 Hz, 1H), 3.05-3.16 (m, 2H), 2.97- 3.04 (m, 1H), 1.87-1.96 (m, 2H)18-9

363.1 0.47 min Q METHANOL-d4 δ 8.27 (d, J = 2.3 Hz, 1H), 8.09 (d, J =10.0 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.70-7.75 (m, J = 1.5 Hz, 1H),7.46 (d, J = 9.8 Hz, 1H), 7.30-7.36 (m, 2H), 6.54 (dd, J = 2.4, 1.9 Hz,1H), 3.63-3.69 (m, 4H), 3.49 (bs, 4H), 1.87-1.93 (m, 4H) 18-10

353.1 0.46 min Q DMSO-d6 δ 14.07 (s, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.28(d, J = 10.0 Hz, 1H), 7.96-8.10 (m, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.56(d, J = 10.0 Hz, 1H), 7.37-7.49 (m, 2H), 6.56 (dd, J = 2.4, 1.9 Hz, 1H),4.81 (t, J = 5.3 Hz, 1H), 4.13-4.45 (m, 2H), 3.38-3.49 (m, 2H),2.89-3.14 (m, 2H), 2.60- 2.84 (m, 3H) 18-11

363.2 0.47 min Q METHANOL-d4 δ 8.17 (d, J = 2.5 Hz, 1H), 8.04 (d, J =9.6 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 1.5 Hz, 1H),7.28-7.36 (m, 2H), 7.10 (d, J = 10.1 Hz, 1H), 6.47-6.55 (m, 1H),3.63-3.77 (m, 2H), 3.59 (d, J = 11.1 Hz, 1H), 3.51 (d, J = 10.6 Hz, 1H),2.93-3.10 (m, 2H), 2.13 (t, J = 7.1 Hz, 2H), 1.81-1.98 (m, 4H) 18-12

351.1 0.49 min Q METHANOL-d4 δ 8.02 (d, J = 2.5 Hz, 1H), 7.90 (d, J =10.1 Hz, 1H), 7.69- 7.75 (m, 2H), 7.30-7.36 (m, 2H), 7.24 (d, J = 10.1Hz, 1H), 6.48-6.51 (m, 1H), 3.66-3.82 (m, 5H), 1.72 (ddd, J = 12.9, 8.1,4.3 Hz, 2H), 1.57- 1.66 (m, 2H), 1.25 (s, 3H) 18-13

365.2 0.43 min Q CHLOROFORM-d δ 13.71 (br. s, 1H), 7.86 (d, J = 2.5 Hz,1H), 7.72 (d, J = 10.1 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.55 (d, J =8.1 Hz, 1H), 7.23- 7.31 (m, 2H), 7.09 (d, J = 10.1 Hz, 1H), 6.33-6.42(m, 1H), 4.53 (d, J = 11.6 Hz, 1H), 4.15 (d, J = 13.1 Hz, 1H), 3.10 (t,J = 11.4 Hz, 1H), 2.91- 3.02 (m, 1H), 2.58 (br. s, 1H), 2.39- 2.53 (br.s, 6H), 2.02-2.14 (m, 1H), 1.83-1.93 (m, 1H), 1.50-1.71 (m, 2H) 18-14

407.3 0.46 min Q CHLOROFORM-d δ 13.83 (br. s, 1H), 7.86 (d, J = 2.5 Hz,1H), 7.65- 7.71 (m, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.54 (d, J = 8.6 Hz,1H), 7.23-7.30 (m, 1H), 7.17 (s, 1H), 6.73 (d, J = 9.1 Hz, 1H),6.34-6.40 (m, 1H), 4.54 (br. s, 1H), 4.21 (br., m, 1H), 2.29 (s, 3H),1.96 (dd, J = 12.4, 3.3 Hz, 2H), 1.49 (br. s, 2H), 1.21 (s, 6H), 1.15(s, 6H) 18-15

351.1 0.48 min Q DMSO-d6 δ 8.59 (d, J = 2.3 Hz, 1H), 8.24 (d, J = 10.3Hz, 1H), 7.98-8.07 (m, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 10.0Hz, 1H), 7.39-7.48 (m, 2H), 6.56 (dd, J = 2.4, 1.9 Hz, 1H), 3.54-3.66(m, 2H), 3.35 (s, 2H), 2.80-2.9 4 (m, 2H), 1.07 (s, 6H) 18-16

407.1 0.46 min Q METHANOL-d4 δ ppm 8.28 (d, J = 2.51 Hz, 1H), 8.07 (d, J= 9.54 Hz, 1H), 7.83 (d, J = 8.28 Hz, 1H), 7.74 (d, J = 1.76 Hz, 1H),7.24-7.38 (m, 2H), 7.09 (d, J = 9.29 Hz, 1H), 6.50- 6.59 (m, 1H), 3.79(t, J = 5.52 Hz, 2H), 3.49-3.68 (m, 4H), 3.27-3.32 (m, 2H), 3.21 (q, J =11.29 Hz, 2H), 3.11 (t, J = 5.40 Hz, 2H), 2.00-2.25 (m, 4H) 18-17

349.2 0.46 min Q DMSO-d6 δ ppm 8.49 (d, J = 2.53 Hz, 1H), 8.19 (d, J =9.60 Hz, 1H), 7.93- 7.98 (m, 1H), 7.73 (d, J = 1.52 Hz, 1H), 7.38-7.44(m, 2H), 7.18 (d, J = 10.11 Hz, 1H), 6.50-6.55 (m, 1H), 3.75 (dd, J =11.12, 8.08 Hz, 2H), 3.41 (dd, J = 11.12, 3.54 Hz, 2H), 3.04 (dd, J =10.86, 6.82 Hz, 2H), 2.94 (dd, J = 7.07, 3.54 Hz, 2H), 2.75 (dd, J =11.12, 3.03 Hz, 2H), 2.63- 2.71 (m, 1H) 18-18

323.4 0.40 min Q DMSO-d6 δ 9.83 (br. s, 1H), 8.86 (br. s, 2H), 8.30-8.54(m, 2H), 7.71 (dd, J = 16.1, 9.5 Hz, 2H), 7.06 (s, 1H), 6.81-6.98 (m,2H), 3.88-3.94 (m, 4H), 3.21-3.33 (m, 4H)

Example 19-1 Synthesis of5-pyrazol-1-yl-2-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-phenol

Step 1

tert-Butyl4-(6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate(151 mg, 0.35 mmol, 100% yield) was prepared from Intermediate 2-1 andtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylateusing General Method 1-4 for Suzuki coupling. LCMS Rt=1.58 min,M+1=434.8 (condition B).

Step 2

5-(1H-Pyrazol-1-yl)-2-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)phenolwas prepared following General Method 3-2 for BBr₃ deprotection.

tert-Butyl4-(6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate(50 mg, 0.12 mmol) was dissolved in DCM (0.6 mL). The solution wascooled to −78° C. and 1 M BBr₃ in DCM (0.6 mL) was added dropwise. Theresulting suspension was removed from the ice bath and stirred at RTovernight. The reaction was quenched with water, diluted with MeOH thenadsorbed onto a MeOH conditioned SCX column. The column was washedseveral times (5-7 column volumes) with MeOH then eluted with 2 N NH₃ inMeOH to provide the desired product,5-(1H-pyrazol-1-yl)-2-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)phenol,(9.7 mg, 0.03 mmol, 25% yield). LCMS Rt=0.49 min, M+1=320.1 (LCMS methodQ). ¹H NMR (DMSO-d6) δ 8.64 (d, J=2.3 Hz, 1H), 8.52 (d, J=9.5 Hz, 1H),8.19 (dd, J=9.0, 3.0 Hz, 2H), 7.80 (d, J=1.3 Hz, 1H), 7.43-7.61 (m, 2H),6.89-7.03 (m, 1H), 6.52-6.66 (m, 1H), 3.56-3.73 (m, 2H), 3.02-3.15 (m,2H), 2.66-2.74 (m, 2H).

Example 19-2 Synthesis of2-(6-piperidin-4-yl-pyridazin-3-yl)-5-pyrazol-1-yl-phenol

To a round-bottomed flask containing 10% Pd/C (27.7 mg, 0.026 mmol), wasadded5-pyrazol-1-yl-2-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-phenol(Example 19-1) (166 mg, 0.52 mmol) in MeOH (2.5 mL). H₂ was bubbledthrough the solution for 5 min, then the reaction was stirred under H₂at 55 psi at RT. After 18 hr, the reaction mixture was filtered throughcelite and washed with MeOH. The solvent was removed in vacuo and theresulting oil was dissolved in MeOH then adsorbed onto a MeOHconditioned SCX column. The column was washed several times (5-7 columnvolume) with MeOH then eluted with 2 N NH₃ in MeOH to provide thedesired product,2-(6-(piperidin-4-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol (19.8 mg,0.06 mmol, 11% yield). LCMS Rt=0.48 min, M+1=322.6 (LCMS method Q). ¹HNMR (DMSO-d6) δ 8.63 (d, J=2.5 Hz, 1H), 8.50 (d, J=9.3 Hz, 1H), 8.15 (d,J=8.5 Hz, 1H), 7.76-7.92 (m, 2H), 7.47-7.56 (m, 2H), 6.59 (dd, J=2.5,1.8 Hz, 1H), 3.24 (s, 2H), 3.07-3.19 (m, 1H), 2.84 (td, J=12.2, 2.4 Hz,2H), 2.00 (s, 2H), 1.77-1.92 (m, 2H).

The following compounds were prepared using similar procedures as inExample 19-1 and 19-2:

LCMS M + 1, Rt, Example Compound conditions ¹H NMR 400 MHz 19-3

304.1 0.50 min Q DMSO-d6 δ 12.49 (br. s, 1H), 8.67 (s, 1H), 8.55 (d, J =9.3 Hz, 1H), 8.18 (d, J = 9.3 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.76(d, J = 8.3 Hz, 1H), 7.49 (s, 1H), 7.26-7.40 (m, 2H), 6.88-7.04 (m, 1H),3.57-3.66 (m, 2H), 3.02-3.12 (m, 2H), 2.64- 2.76 (m, 2H) 19-4

320.1 0.41 min Q DMSO-d6 δ 12.47 (br. s, 1H), 9.95 (s, 1H), 8.98 (br. s,2H), 8.46-8.65 (m, 2H), 8.23 (d, J = 9.5 Hz, 1H), 7.78 (d, J = 8.8 Hz,1H), 7.12 (s, 1H), 6.84-7.01 (m, J = 8.2, 5.7, 2.1 Hz, 3H), 3.87-3.96(m, 2H), 3.37- 3.46 (m, 2H), 2.90-2.99 (m, 2H) 19-5

376.1 0.49 min Q DMSO-d6 δ 9.95 (br. s, 1H), 8.81 (br. s, 2H), 8.51-8.67(m, 2H), 8.25 (d, J = 9.3 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.12 (s,1H), 6.83- 7.03 (m, 3H), 2.90 (s, 2H), 1.58 (s, 6H), 1.48 (s, 6H) 19-6

334.4 0.42 min Q DMSO-d6 δ 12.39 (br. s, 1H). 10.41 (br. s, 1H), 9.92(br. s, 1H), 8.41-8.72 (m, 2H), 8.23 (d, J = 9.3 Hz, 1H), 7.78 (d, J =8.8 Hz, 1H), 7.12 (s, 1H), 6.82-7.01 (m, 3H), 4.05-4.22 (m, 1H), 3.91(d, J = 16.9 Hz, 1H), 3.68 (br. s., 1H), 3.23-3.31 (m, 1H), 2.96-3.16(m, 2H), 2.92 (d, J = 4.0 Hz, 3H) 19-7

322.4 0.42 min Q DMSO-d6 δ 8.81-9.16 (m, 1H), 8.59-8.79 (m, 1H), 8.53(d, J = 9.1 Hz, 1H), 8.47 (s, 1H), 7.86 (d, J = 9.1 Hz, 1H), 7.76 (d, J= 9.1 Hz, 1H), 7.12 (s, 1H), 6.85-7.03 (m, 2H), 3.43 (d, J = 12.6 Hz,2H), 3.23-3.35 (m, 1H), 3.08 (q, J = 12.0 Hz, 2H), 1.93-2.27 (m, 4H)

Example 20-1 Synthesis of3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalene-2,7-diol

Step 1

Following representative procedure GENERAL METHOD 1-1, Suzukicross-coupling, Intermediate 3-1 and Intermediate 1-3 were reacted toprovide7-(benzyloxy)-6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalen-2-ol(163 mg, 0.337 mmol). LCMS Rt=1.12 min, M+1=484.3 (condition B).

Step 2:3-(6-((2,2,6,6-Tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalene-2,7-diol

(33 mg, 0.084 mmol, 54.1% yield) was prepared from7-(benzyloxy)-6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalen-2-olfollowing GENERAL METHOD 4-1 for hydrogenolysis. LCMS Rt=0.50 min (LCMSmethod Q); MS (M+1)=394.5. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.40 (br. s,1H), 9.84 (s, 1H), 8.47 (d, J=9.54 Hz, 1H), 8.43 (s, 1H) 7.74 (d, J=8.78Hz, 1H), 7.40 (d, J=9.54 Hz, 1H), 7.09 (s, 1H), 6.87-6.95 (m, 2H),5.62-5.73 (m, 1H), 2.11 (d, J=9.29 Hz, 2H), 1.39 (br. s, 2H). 1.25 (br.s, 6H), 1.12 (br. s, 6H).

Example 20-2 Synthesis of3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol

Step 1

Following representative procedure GENERAL METHOD 1-1, Suzukicross-coupling, Intermediate 3-1 and Intermediate 1-1 were reacted toprovide7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(1.25 g, 2.36 mmol, 89% yield). LCMS R_(t)=0.97 min, M+1=497.8(condition C). ¹H NMR (400 MHz, METHANOL-d4) δ ppm 7.91 (s, 1H), 7.76(d, J=9.54 Hz, 2H), 7.66 (d, J=8.78 Hz, 2H), 7.34-7.40 (m, 2H), 7.31 (s,2H), 7.18-7.27 (m, 2H), 6.97-7.05 (m, 2H), 6.91 (dd, J=8.78, 2.26 Hz,1H), 5.18 (m, 3H), 2.92 (s, 3H), 1.60-1.68 (m, 2H), 1.45-1.55 (m, 2H),1.32 (s, 6H), 1.18 (s, 6H).

Step 2

3-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol(43 mg, 0.097 mmol, 48.2% yield) was prepared from7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-olfollowing GENERAL METHOD 4-1 for hydrogenolysis. LCMS Rt=0.48 min,M+1=407.2 (LCMS method Q). ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.27 (d,J=10.04 Hz, 1H), 8.20 (br. s, 3H), 7.71 (d, J=8.78 Hz, 1H), 7.35 (d,J=9.79 Hz, 1H), 7.05 (s, 1H), 6.85-6.94 (m, 2H), 5.27 (br. s, 1H), 3.03(s, 3H), 1.71-1.91 (m, 4H), 1.54 (s, 6H), 1.39 (s, 6H).

Example 20-3 Synthesis of3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol

Step 1

Following representative procedure GENERAL METHOD 1-1, Suzukicross-coupling, Intermediate 3-1 and Intermediate 1-2 were reacted toprovide7-(benzyloxy)-6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(49 mg, 0.096 mmol, 52% yield). LCMS Rt=1.16 min (condition C); MS(M+1)=483.8.

Step 2

3-(6-((2,2,6,6-Tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol(3 mg, 0.007 mmol, 38% yield) was prepared from7-(benzyloxy)-6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-olfollowing GENERAL METHOD 4-1 for hydrogenolysis. LCMS Rt=0.47 min (LCMSmethod Q); MS (M+1)=393.1. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.42 (d,J=9.29 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.53 Hz, 1H), 7.64 (d, J=9.54Hz, 1H), 7.15 (s, 1H), 6.96-7.02 (m, 2H), 4.51 (t, J=11.92 Hz, 1H),2.96-3.04 (m, 1H), 2.68 (s, 1H), 2.35 (dd, J=13.55, 3.01 Hz, 2H),1.69-1.75 (m, 2H), 1.64 (s, 6H), 1.56 (s, 6H).

Example 20-4 Synthesis of[3-(7-hydroxy-6-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-yloxy)-propyl]-carbamicacid tert-butyl ester

Step 1: tert-Butyl(3-((7-(benzyloxy)-6-bromonaphthalen-2-yl)oxy)propyl)carbamate

Following GENERAL METHOD 5-1 for phenol alkylation using7-(benzyloxy)-6-bromonaphthalen-2-ol (506.5 mg, 1.54 mmol) andtert-butyl 3-bromopropylcarbamate (409 mg, 1.72 mmol) and after columnchromatography (eluting with 3-80% EtOAc/heptane) tert-butyl(3-((7-(benzyloxy)-6-bromonaphthalen-2-yl)oxy)propyl)carbamate wasobtained as an off-white solid (706 mg, 94% yield). MS (M-Boc)=388.3. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (s, 1H), 7.59 (d, J=9.60 Hz, 1H),7.54 (d, J=8.08 Hz, 2H), 7.42 (t, J=7.58 Hz, 2H), 7.32-7.37 (m, 1H),7.13 (s, 1H), 7.05-7.00 (m, 2H), 5.26 (s, 2H), 4.68 (br. s, 1H), 4.14(t, J=6.06 Hz, 2H), 3.37 (q, J=6.40 Hz, 2H), 2.09-2.01 (m, 2H), 1.47 (s,9H).

Step 2: tert-Butyl(3-((7-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)propyl)carbamate

Following GENERAL METHOD 2-1 for boronate ester formation usingtert-butyl(3-((7-(benzyloxy)-6-bromonaphthalen-2-yl)oxy)propyl)carbamate (659 mg,1.36 mmol) affords tert-butyl(3-((7-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)propyl)carbamateas an an off-white solid (662 mg, 87% yield). MS (M-^(t)Bu)=478.0. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 8.16 (s, 1H), 7.65-7.72 (m, 3H), 7.39(t, J=7.33 Hz, 2H), 7.29-7.34 (m, 1H), 7.08 (s, 1H), 7.04 (d, J=2.53 Hz,1H), 6.98 (dd, J=8.84, 2.27 Hz, 1H), 5.23 (s, 2H), 4.70 (br. s, 1H),4.16 (t, J=6.06 Hz, 2H), 3.38 (q, J=6.57 Hz, 2H), 2.00-2.10 (m, 2H),1.47 (s, 9H), 1.41 (s, 12H).

Step 3: tert-Butyl(3-((7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yl)oxy)propyl)carbamate

Intermediate 1-1 (242.5 mg, 0.86 mmol) and tert-butyl(3-((7-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)propyl)carbamate(662 mg, 1.18 mmol) were reacted following GENERAL METHOD 1-1 for Suzukicoupling with the following modifications: Instead of SCX purification,the crude material was purified by flash chromatography (eluting with1-15% 7N NH₃ in MeOH/DCM) to afford a yellow oil. The oil was trituratedwith Et₂O then concentrated in vacuo to dryness affording tert-butyl(3-((7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yl)oxy)propyl)carbamatea pale-yellow solid (492 mg, 83% yield). MS (M+1)=654.8.

Step 4: tert-Butyl(3-((7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yl)oxy)propyl)carbamate

Pd/C (10% wt 80 mg, 0.075 mmol) was added to a EtOAc (5 mL)/MeOH (5 mL)solution of tert-butyl(3-((7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yl)oxy)propyl)carbamate(492 mg, 0.752 mmol) at RT. The reaction mixture was evacuated andfilled with H₂ (2×) then stirred at RT under H₂ (1 atm) for 16 h. Thereaction mixture was filtered through celite washing with MeOH, washthen concentrated in vacuo to dryness affording a tan solid. The solidwas dissolved in DCM then adsorbed onto a silica bound amine column(Si—NH₂ column 10 g, Varian brand, Bond Elut NH₂). The column was thenwashed with MeOH (150 mL) then the solvent was concentrated in vacuoaffording a yellow oil. The oil was dissolved in Et₂O then concentratedin vacuo affording the title compound as a beige solid (386 mg, 91%yield). MS (M+1)=564.3; ¹H NMR (400 MHz, DMSO-d6) δ ppm 13.29 (br. s,1H), 8.34 (s, 1H), 8.28 (d, J=10.10 Hz, 1H), 7.76 (d, J=9.09 Hz, 1H),7.34 (d, J=10.11 Hz, 1H), 7.15 (s, 1H), 7.08 (d, J=2.53 Hz, 1H), 6.94(dd, J=9.09, 2.53 Hz, 1H), 4.89-5.06 (m, 1H), 4.56 (s, 1H), 4.09 (t,J=6.32 Hz, 2H), 3.09-3.16 (m, 2H), 2.98 (s, 3H), 1.80-1.95 (m, 2H),1.50-1.61 (m, 2H), 1.44 (t, J=12.38 Hz, 2H), 1.38 (s, 9H), 1.27 (s, 6H),1.10 (s, 6H).

Example 20-5 Synthesis of7-(3-amino-propoxy)-3-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-ol

TFA (1.5 ml, 19.47 mmol) was added to a solution of Example 20-4 (289.4mg, 0.513 mmol) in DCM (6 ml) at RT. The reaction mixture was stirred atRT for 30 min, diluted with MeOH then adsorbed onto a MeOH conditionedSCX column (10 g). The column was washed several times with MeOH theneluted with 3 N NH₃ in MeOH. Evaporation of the solvent afforded thetitle compound as a beige solid (178 mg, 75% yield). LCMS Rt=0.44 min(LCMS method Q); MS (M+1)=464.2. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.35(s, 1H), 8.28 (d, J=9.60 Hz, 1H), 7.77 (d, J=9.09 Hz, 1H), 7.36 (d,J=9.60 Hz, 1H), 7.16-7.18 (m, 1H), 7.11 (d, J=2.53 Hz, 1H), 6.96 (dd,J=8.84, 2.27 Hz, 1H), 4.91-5.04 (m, 1H), 4.56 (s, 1H), 4.17 (t, J=6.32Hz, 2H), 2.98 (s, 3H), 2.88 (d, J=7.07 Hz, 2H), 1.90-2.05 (m, 2H),1.46-1.62 (m, 4H), 1.30 (s, 6H), 1.14 (s, 6H).

Example 20-6 Synthesis ofN-[3-(7-hydroxy-6-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-yloxy)-propyl]-acetamide

N-Acetoxysuccinimide (98 mg, 0.624 mmol) was added to a solution ofExample 20-5 (50 mg, 0.108 mmol) and TEA (0.747 ml, 5.39 mmol) in DMSO(2 ml) at RT. The reaction mixture was stirred at RT for 30 min thenconcentrated in vacuo to remove excess Et₃N. The resulting residue waspurified by preparative HPLC (eluting with 5-80% MeCN/H₂O with 0.1% TFAmodifier). The appropriate fractions containing product were combinedthen adsorbed onto a MeOH conditioned SCX column (5 g, BSA Varianbrand). The column was washed several times with MeOH then eluted with 3N NH₃ in MeOH. Evaporation of the solvent afforded a yellow oil. Et₂Owas added to the oil then concentrated to dryness affording the titlecompound as a yellowish orange solid (30 mg, 55% yield). LCMS Rt=0.52min (LCMS method Q); MS (M+1)=506.2. ¹H NMR (400 MHz, DMSO-d6) δ ppm13.27 (br. s, 1H), 8.35 (s, 1H), 8.28 (d, J=10.10 Hz, 1H), 7.77 (d,J=9.09 Hz, 2H), 7.35 (d, J=9.60 Hz, 1H), 7.17 (s, 1H), 7.09 (d, J=2.02Hz, 1H), 6.95 (dd, J=9.09, 2.53 Hz, 1H), 4.92-5.04 (m, 1H), 4.11 (t,J=6.32 Hz, 2H), 3.20-3.28 (m, 2H), 2.98 (s, 3H), 1.87-1.96 (m, 2H), 1.82(s, 3H), 1.55-1.63 (m, 2H), 1.44-1.55 (m, 2H), 1.30 (s, 6H), 1.14 (s,6H).

Example 20-7 Synthesis of7-(3-hydroxypropoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

Step 1: 3-(benzyloxy)-6-(3-(benzyloxy)propoxy)-2-bromonaphthalene

Following GENERAL METHOD 5-1 for phenol alkylation, Cs₂CO₃ (485 mg,1.489 mmol) was added to a solution of7-(benzyloxy)-6-bromonaphthalen-2-ol (490 mg, 1.489 mmol) in acetone(14.90 mL) at RT. The reaction mixture was stirred for 5 min then((3-bromopropoxy)methyl)benzene (682 mg, 2.98 mmol) was added, followedby addition of NaI (446 mg, 2.98 mmol). The reaction mixture was heatedto 60° C. and stirred overnight, then filtered, washed with acetone andconcentrated in vacuo. The resulting residue was partitioned betweenEt₂O (60 mL) and water (20 mL). After separation, the organic layer waswashed with saturated aq. sodium sulfite solution (20 mL), 2 M Na₂CO₃,and brine. The organic layer was then dried over MgSO₄, filtered, andconcentrated in vacuo. Silica gel chromatography (10-60% EtOAc/heptane)afforded 3-(benzyloxy)-6-(3-(benzyloxy)propoxy)-2-bromonaphthalene (422mg, 0.884 mmol, 60% yield) as a white solid (eluting at 30% EtOAc). LCMSRt=1.81 min (condition C); LCMS (M+1)=479.9.

Step 2:2-(3-(Benzyloxy)-6-(3-(benzyloxy)propoxy)naphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(355 mg, 0.677 mmol, 81% yield) was prepared from the bromide usingfollowing GENERAL METHOD 2-1 for boronate ester formation. LCMS Rt=1.89min (condition C); MS (M+1)=525.3. Step 3

6-(3-(benzyloxy)-6-(3-(benzyloxy)propoxy)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(59 mg, 0.091 mmol, 27% yield) was prepared via Suzuki reaction from theboronic ester and Intermediate 1-1 following GENERAL METHOD 1-1. LCMSRt=1.50 min (condition C); MS (M+1)=645.3.

Step 4

7-(3-Hydroxy-propoxy)-3-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-ol(10 mg, 0.021 mmol, 23% yield) was prepared from6-(3-(benzyloxy)-6-(3-(benzyloxy)propoxy)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-aminefollowing GENERAL METHOD 4-1 for hydrogenolysis. LCMS Rt=0.53 min (LCMSmethod Q); MS (M+1)=465.2. ¹H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm7.97-8.08 (m, 2H), 7.63-7.72 (m, 1H), 7.19 (d, J=9.79 Hz, 1H), 7.04-7.12(m, 1H), 7.01 (d, J=8.28 Hz, 1H), 6.89-6.97 (m, 1H), 4.99 (br. s, 1H),4.13-4.24 (m, 2H), 3.74-3.85 (m, 2H), 3.30-3.38 (m, 1H) 2.97 (br. s,3H), 2.12 (br. s, 1H) 2.01-2.10 (m, 2H), 1.65-1.73 (m, 2H), 1.39-1.50(m, 2H), 1.34 (br. s, 6H), 1.17 (br. s, 6H).

Example 20-8 Synthesis of7-(3-methoxypropoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

7-(3-methoxypropoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(15 mg, 0.031 mmol, 27% yield) was prepared in a similar manner toExample 21-7. LCMS Rt=0.53 min (LCMS method Q); MS (M+1)=479.2. ¹H NMR(400 MHz, DICHLOROMETHANE-d2) δ ppm 8.01-8.07 (m, 2H), 7.69 (d, J=9.09Hz, 2H), 7.20 (s, 1H), 7.09 (d, J=9.85 Hz, 1H), 7.00 (d, J=2.02 Hz, 1H),6.95 (d, J=8.84 Hz, 1H), 5.42 (t, J=12.51 Hz, 1H), 4.15 (t, J=6.32 Hz,2H), 3.58 (t, J=6.19 Hz, 2H), 3.35 (s, 3H), 3.01 (s, 3H), 1.94-2.14 (m,4H), 1.77 (dd, J=13.39, 3.28 Hz, 2H), 1.58 (s, 6H), 1.51 (s, 6H).

Example 20-9 Synthesis of7-(2-morpholinoethoxy)-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalen-2-ol

7-(2-morpholinoethoxy)-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalen-2-olwas prepared in a similar manner to Example 21-7. LCMS Rt=0.43 min (LCMSmethod Q); MS (M+1)=507.3. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.49 (d,J=9.79 Hz, 1H), 8.34 (s, 1H) 7.79 (d, J=9.03 Hz, 1H), 7.36 (d, J=9.54Hz, 1H), 7.24 (s, 1H), 7.12 (d, J=2.26 Hz, 1H), 7.01 (dd, J=9.03, 2.51Hz, 1H), 5.80-5.91 (m, 1H), 4.29 (t, J=5.40 Hz, 2H), 3.73-3.79 (m, 4H),2.91 (t, J=5.40 Hz, 2H), 2.63-2.72 (m, 4H), 2.51 (dd, J=13.80, 4.02 Hz,2H), 1.85 (dd, J=13.43, 10.92 Hz, 2H), 1.64 (s, 6H), 1.56 (s, 6H).

Example 21-1 Synthesis of3-(6-(piperidin-4-ylmethyl)pyridazin-3-yl)naphthalen-2-ol

Step 1: tert-Butyl4-((6-chloropyridazin-3-yl)methyl)piperidine-1-carboxylate

To a flask containing tert-butyl 4-methylenepiperidine-1-carboxylate(487 mg, 2.47 mmol) was added 0.5 M 9-borabicyclo[3.3.1]nonane in THF(5.4 mL, 2.72 mmol). The reaction was refluxed at 65° C. for 1 h thenadded to a degassed suspension of 3,6-dichloropyridazine (368 mg, 2.47mmol), K₂CO₃ (1.0 g, 7.41 mmol), and PdCl₂(dppf)CH₂Cl₂ (101 mg, 0.12mmol) in 1,4-dioxane (5.2 mL) and water (0.88 mL). The resultingreaction mixture was heated at 60° C. for 3 h then cooled to RT anddiluted with EtOAc. The suspension was filtered through celite andconcentrated in vacuo. Silica gel chromatography, eluting with 0-100%EtOAc/heptane, afforded the product, tert-butyl4-((6-chloropyridazin-3-yl)methyl)piperidine-1-carboxylate (376 mg, 1.21mmol, 49% yield). ¹H NMR (DMSO-d6) δ: 7.85 (d, J=8.8 Hz, 1H), 7.70 (d,J=8.8 Hz, 1H), 3.74-4.05 (m, 2H), 2.85 (d, J=7.3 Hz, 2H), 2.54-2.79 (m,2H), 1.82-2.01 (m, 1H), 1.48-1.62 (m, 2H), 1.38 (s, 9H), 0.97-1.18 (m,2H).

Step 2

tert-butyl4-((6-(3-methoxynaphthalen-2-yl)pyridazin-3-yl)methyl)piperidine-1-carboxylate(63 mg, 0.145 mmol, 45% yield) was prepared from tert-butyl4-((6-chloropyridazin-3-yl)methyl)piperidine-1-carboxylate and(3-methoxynaphthalen-2-yl)boronic acid using GENERAL METHODS 1-4.

Step 3

3-(6-(Piperidin-4-ylmethyl)pyridazin-3-yl)naphthalen-2-ol (31 mg, 0.097mmol, 67% yield) was prepared from tert-butyl4-((6-(3-methoxynaphthalen-2-yl)pyridazin-3-yl)methyl)piperidine-1-carboxylateusing GENERAL METHOD3-2. LCMS Rt=0.53 min, M+1=320.2 (LCMS method Q); ¹HNMR (DMSO-d6) δ 8.62 (s, 1H), 8.51 (d, J=9.0 Hz, 1H), 7.93 (d, J=8.0 Hz,1H), 7.82 (d, J=9.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.48 (ddd, J=8.2,6.9, 1.3 Hz, 1H), 7.29-7.40 (m, 2H), 2.85-2.99 (m, 4H), 2.41-2.48 (m,2H), 1.84-1.99 (m, 1H), 1.48-1.65 (m, 2H), 1.10-1.27 (m, 2H).

Example 21-2 Synthesis of5-(1H-pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol

Step 1: 2,2,6,6-Tetramethyl-4-methylenepiperidine trifluoroacetate

To a 100 mL flask containing methyltriphenylphosphonium bromide (5.2 g,14.5 mmol) in ether (8 mL) cooled to 0° C. was added potassiumtert-butoxide (2.2 g, 19.3 mmol). The resulting suspension was stirredfor 0.5 h at 0° C. followed by the dropwise addition of2,2,6,6-tetramethylpiperidin-4-one (1.0 g, 6.44 mmol) in ether (5 mL).The resulting mixture was stirred at RT overnight at which timeadditional potassium tert-butoxide (0.72 g, 6.44 mmol) andmethyltriphenylphosphonium bromide (1.7 g, 4.83 mmol) were added. Thereaction was stirred at RT for 4 h then cooled to 0° C. and quenchedwith water, acidified with 1 M HCl aqueous solution and washed withether (3×). The aqueous mixture was adjusted to pH 10 with 2 M NaOH andextracted with ether (3×). The organic extract was acidified withtrifluoracetic acid, dried with sodium sulfate and concentrated in vacuoto afford desired product as a brown oil2,2,6,6-tetramethyl-4-methylenepiperidine trifluoroacetate salt (1.7 g,4.46 mmol, 70% yield), ¹H NMR (DMSO-d6) δ 8.53 (br. s, 2H), 5.00 (s,2H), 2.20-2.30 (m, 4H), 1.33 (s, 12H).

Step 2:3-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine

To a flask containing 2,2,6,6-tetramethyl-4-methylenepiperidinetrifluoroacetate (250 mg, 0.936 mmol) was added 0.5 M9-borabicyclo[3.3.1]nonane in THF (3.7 mL, 1.87 mmol). The reaction wasrefluxed at 65° C. for 1 h, then 0.5 M 9-borabicyclo[3.3.1]nonane in THF(0.75 mL, 0.375 mmol) was added and reflux continued for 1 h. Theresulting mixture was added to a degassed suspension of Intermediate 2-1(268 mg, 0.936 mmol), K₂CO₃ (388 mg, 2.81 mmol), and PdCl₂(dppf).CH₂Cl₂(38 mg, 0.05 mmol) in 1,4-dioxane (2.7 mL) and water (0.45 mL) andheated at 90° C. overnight then cooled to RT and diluted with EtOAc. Thesuspension was filtered through celite and concentrated in vacuo. Theproduct was adsorbed onto a methanol-conditioned SCX (5 g) column. Thecolumn was washed several times with methanol then eluted with 2 Nammonia in methanol. The product was collected and concentrated in vacuoto afford the crude product.3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine.LCMS Rt=0.92 min, M+1=406.3.

Step 3

5-(1H-Pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol(56.1 mg, 0.143 mmol, 18% yield) was prepared from3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazineusing GENERAL METHOD 3-1. LCMS Rt=0.52 min, M+1=392.3 (LCMS method Q);¹H NMR (DMSO-d6) δ 8.64 (d, J=2.5 Hz, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.17(d, J=8.5 Hz, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H),7.45-7.59 (m, 2H), 6.59 (dd, J=2.5, 1.8 Hz, 1H), 2.84 (d, J=7.0 Hz, 2H),2.21-2.42 (m, 1H), 1.46 (d, J=11.8 Hz, 2H), 0.67-1.30 (m, 14H).

Example 22-1 Synthesis of3-methoxy-2-(6-(methyl(2,2,6-trimethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol

Step 1: Methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate

To a mixture of methyl 4-bromo-3,5-dihydroxybenzoate (18.8 g, 76 mmol)and potassium carbonate (5.26 g, 38.1 mmol) in DMF (190 mL) was addedbenzyl bromide (3.17 mL, 26.6 mmol). The mixture was stirred overnight,diluted with 200 mL water and acidified to pH 1 by slow addition ofconcentrated hydrochloric acid. The solution was extracted with 1:1ethyl acetate/ether (6×) and the combined extracts were washed withwater (8×), saturated sodium bicarbonate, brine, dried over magnesiumsulfate and concentrated to an orange solid. The solids were suspendedin DCM (200 mL) and stirred overnight. The solids (primarily unreacted4-bromo-3,5-dihydroxybenzoate) were removed by filtration and thefiltrate was concentrated to an orange oil which was purified by columnchromatography (80 g silica gel, 2:1 DCM in heptane elution, followed byDCM elution) to provide methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate(4.66 g). MS (M+1)=337.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32-7.57(m, 6H), 7.26 (d, J=1.52 Hz, 1H), 5.77 (s, 1H), 5.22 (s, 2H), 3.93 (s,3H) as well as the di-benzylated methyl3,5-bis(benzyloxy)-4-bromobenzoate (1.8 g).

Step 2: Methyl 3-(benzyloxy)-4-bromo-5-methoxybenzoate

To a mixture of methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (3.69 g,10.94 mmol) and potassium carbonate (3.03 g, 21.98 mmol) in DMF (27 mL)was added methyl iodide (0.753 mL, 12.04 mmol). The mixture was stirredovernight after which time it was diluted with water and extracted withethyl acetate (4×). The combined extracts were washed with water (8×),brine, dried over magnesium sulfate and concentrated to provide methyl3-(benzyloxy)-4-bromo-5-methoxybenzoate as a white solid (3.72 g). MS(M+1)=351.1; ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.31-7.59 (m, 7H),5.24 (s, 2H), 3.99 (s, 3H), 3.95 (s, 3H).

Step 3: 3-(Benzyloxy)-4-bromo-5-methoxybenzoic acid

To a solution of methyl 3-(benzyloxy)-4-bromo-5-methoxybenzoate (3.72 g,10.59 mmol) in 1:1 MeOH/THF (50 mL) was added aqueous sodium hydroxide(1 M, 53.0 mL, 53.0 mmol). After 10 minutes the volatiles were removedunder reduced pressure and the solution acidified to pH 1 by addition ofconcentrated hydrochloric acid resulting in formation of a thick whiteprecipitate. The mixture was extracted with ethyl acetate (2×), and DCM(3×). The combined extracts were washed with brine, dried over magnesiumsulfate and concentrated to provide3-(benzyloxy)-4-bromo-5-methoxybenzoic acid as a white solid (3.41 g).MS (M−1)=335.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21-7.49 (m, 7H),5.16 (s, 2H), 3.91 (s, 3H).

Step 4: 3-(Benzyloxy)-4-bromo-5-methoxy-N-(prop-2-yn-1-yl)benzamide

To a suspension of 3-(benzyloxy)-4-bromo-5-methoxybenzoic acid (2.0 g,5.93 mmol) and 4 drops of DMF in DCM (40 mL) was slowly added oxalylchloride (0.57 mL, 6.52 mmol). After three hours the solvent was removedand the residue redissolved into DCM (10 mL). To this solution wasslowly added a mixture of propargylamine (0.46 mL, 7.12 mmol) andtriethylamine (2.5 mL, 17.8 mmol) in DCM (2 mL). After 30 minutes thesolution was diluted with ether, washed with water (2×), 1 Mhydrochloric acid (2×), water, saturated sodium bicarbonate, brine,dried over magnesium sulfate and concentrated to a yellow solid. Thesolid was triturated with diethyl ether and dried under vacuum toprovide 3-(benzyloxy)-4-bromo-5-methoxy-N-(prop-2-yn-1-yl)benzamide(1.88 g) as an off-white solid. MS=374.0 (M+1).

Step 5. 2-(3-(Benzyloxy)-4-bromo-5-methoxyphenyl)-5-methyloxazole

To a solution of3-(benzyloxy)-4-bromo-5-methoxy-N-(prop-2-yn-1-yl)benzamide (0.455 g,1.22 mmol) in dioxane (12 mL) was added sodium hydride (60% wt, 0.146 g,3.65 mmol) and the mixture heated at reflux for six hours. The mixturewas cooled to RT, quenched by slow addition of water and diluted withethyl acetate. The mixture was washed with water, saturated sodiumbicarbonate, brine, dried over magnesium sulfate and concentrated. Flashcolumn chromatography (12 g silica, 2% ethyl acetate in DCM) provided2-(3-(benzyloxy)-4-bromo-5-methoxyphenyl)-5-methyloxazole (198 mg) as anoff-white solid. MS=374 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.55(d, J=7.58 Hz, 2H), 7.43 (t, J=7.33 Hz, 2H), 7.32-7.39 (m, 2H), 7.27 (d,J=2.02 Hz, 1H), 6.89 (d, J=1.01 Hz, 1H), 5.27 (s, 2H), 4.02 (s, 3H),2.44 (d, J=1.52 Hz, 3H).

Step 6: (2-(Benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)boronicacid

To a stirred solution of2-(3-(benzyloxy)-4-bromo-5-methoxyphenyl)-5-methyloxazole (197 mg, 0.526mmol) in THF (1.3 mL) cooled to −78° C. was added n-butyl lithium (2.5 Min hexanes, 232 uL, 0.579 mmol). The solution was stirred for 15 minutesafter which time trimethyl borate (235 uL, 2.11 mmol) was added and thesolution was allowed to slowly warm to RT overnight. The reaction wasquenched by addition of 0.1 M HCl and was diluted with ethyl acetate,washed with water, brine, dried over magnesium sulfate and concentrated.Flash column chromatography (12 g silica, 0-100% ethyl acetate in DCMover 30 column volumes) provided(2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)boronic acid (63mg) as a white foam. MS=340.1 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δppm 7.28-7.46 (m, 5H), 7.25 (d, J=1.01 Hz, 1H), 7.08 (br. s, 1H), 6.85(d, J=1.01 Hz, 1H), 5.17 (s, 2H), 3.95 (s, 3H), 2.38 (d, J=1.52 Hz, 3H).

Step 7:6-(2-(Benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

A mixture of(2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)boronic acid (63mg, 0.186 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineIntermediate 1-1 (35 mg, 0.124 mmol), sodium carbonate (39.4 mg, 0.371mmol) in 3:1 DME/water (825 uL) was degassed with a dry stream ofnitrogen for five minutes. Tetrakis(triphenylphosphine)palladium(0) (21mg, 0.019 mmol) was added and the mixture heated via microwaveirradiation at 150° C. for fifteen minutes. The crude reaction wasfiltered, the filtrate was acidified with 2 M HCl in MeOH, and thenconcentrated to dryness. The residue was redissolved in methanol andadsorbed onto a MeOH conditioned SCX column. The column was washedseveral times (3-4 column volumes) with MeOH then eluted with 3.5 Nammonia in MeOH. Evaporation of the eluent afforded the product as alight brown foam. Flash column chromatography (4 g silica gel, 0-40% 7 Nammonia in MeOH gradient in DCM over 30 column volumes) provided6-(2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineas a white solid. MS=542.4 (M+1). ¹H NMR (400 MHz, METHANOL-d4) δ ppm7.45 (d, J=1.01 Hz, 1H), 7.37-7.42 (m, 2H), 7.21-7.33 (m, 5H), 7.14 (d,J=9.60 Hz, 1H), 6.98 (d, J=1.01 Hz, 1H), 5.28 (m, 1H), 5.17 (s, 2H),3.86 (s, 3H), 3.01 (s, 3H), 2.47 (d, J=1.01 Hz, 3H), 1.71 5 (dd, J=12.1,3.7 Hz, 2H), 1.62 (t, J=12.1 Hz, 2H), 1.41 (s, 6H), 1.27 (s, 6H).

Step 8.3-Methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol

To a solution of6-(2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(36 mg, 0.066 mmol) in 1:1 ethyl acetate/MeOH (1.3 mL) under anatmosphere of nitrogen was added palladium on carbon (10% Pd content, 7mg, 6.6 umol). The atmosphere was replaced by hydrogen (balloon) and themixture stirred rapidly at RT overnight. The solution was diluted withDCM and filtered through celite. The filtrate was concentrated to ayellow residue and acidified with HCl in MeOH (produced by slow additionof acetyl chloride (14 uL, 0.199 mmol) to 1 mL MeOH). The solution wasconcentrated under vacuum, the residue redissolved into MeOH, and loadedonto an SCX column preconditioned with MeOH. The column was washed withMeOH (20 mL) and eluted with 3.5 N ammonia in MeOH (20 mL). Evaporationof the eluent afforded the product as a light yellow residue. Sonicationwith diethyl ether resulted in formation of a light yellow solid.Solvent was removed under reduced pressure to provide3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol(22 mg). LCMS Rt=0.54 min (LCMS method Q); MS=352.3 (M+1). ¹H NMR (400MHz, METHANOL-d4) δ ppm 8.22 (d, J=10.11 Hz, 1H), 7.18-7.29 (m, 3H),6.96 (d, J=1.01 Hz, 1H), 5.07-5.20 (m, 1H), 3.98 (s, 3H), 3.03 (s, 3H),2.46 (d, J=1.52 Hz, 3H), 1.73 (dd, J=12.5, 3.4 Hz, 2H), 1.62 (t, J=12.5Hz, 2H), 1.42 (s, 6H), 1.26 (s, 6H).

Example 23-1 Synthesis of2-(6-((6S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

Step 1.3-((6S)-6-(S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-yloxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine

To a solution of3-chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine Intermediate2-1 (32 mg, 0.11 mmol) and(6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-ol(Intermediate 4-1, 32 mg, 0.11 mmol) in DMF (1 mL) was added potassiumtert-butoxide (1 M in THF, 0.45 mL, 0.45 mmol) at 0° C. The reactionmixture was stirred for 1 h at RT. The mixture was then quenched withsaturated ammonium chloride solution (10 mL) and extracted with 10% MeOHin dichloromethane (20 mL). The extract was dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatography(EtOAc/Heptane) to afford 56 mg (94%) of3-((6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-yloxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine:LCMS (m/z, MH⁺): 538.5; ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.05 (d, J=8.1Hz, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.76 (d, J=1.5Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.6, 2.0 Hz, 1H), 6.94 (d,J=9.1 Hz, 1H), 6.54-6.47 (m, 1H), 5.79-5.87 (m, 1H), 3.96 (s, 3H),3.83-3.93 (m, 1H), 3.07-3.17 (m, 1H), 2.13-2.22 (m, 1H), 2.05-2.12 (m,1H), 1.43-1.57 (m, 2H), 1.27 (s, 3H), 1.16 (d, J=6.6 Hz, 3H), 1.14 (s,3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H).

Step 2.2-(6-((6S)-6-((S)-1-Hydroxyethyl)-2,2-dimethylpiperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

To a solution of3-((6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-yloxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine(56 mg, 0.1 mmol) in CH₂Cl₂ (2 mL) was added BBr₃ (1 M in heptane, 0.13mL, 0.13 mmol) dropwise at 0° C. The mixture was stirred overnight. Thereaction mixture was quenched with water and then basicifed withsaturated NaHCO₃ solution. The organic layer was extracted with 10% MeOHin dichloromethane (10 mL×3). The combined extracts were dried overNa₂SO₄ and concentrated in vacuo. Purification by HPLC gave 12 mg (28%)of2-(6-((6S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol:LCMS Rt=0.52 min (LCMS method Q); MS=410.3 (M+1); ¹H NMR (400MHz,METHANOL-d4) δ 8.23 (d, J=9.6 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.86(d, J=8.6 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.32-7.25 (m, 2H), 7.22 (d,J=9.6 Hz, 1H), 6.47-6.43 (m, 1H), 5.59-5.66 (m, 1H), 3.68-3.77 (m, 1H),3.02-3.11 (m, 1H), 2.03-2.15 (m, 2H), 1.49-1.59 (m, 2H), 1.24 (s, 3H),1.11 (d, J=6.4 Hz, 3H), 1.10 (s, 3H).

Preparation 9 Intermediate 5-1 Synthesis of7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

7-(Benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(1.25 g, 2.366 mmol, 89% yield) was prepared from the7-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol(1.45 g, 3.85 mmol) and Intermediate 1-1 (0.75 g, 2.65 mmol) usingGeneral method 1-1 for Suzuki coupling. M+1=497.8. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.91 (s, 1H), 7.76 (d, J=9.54 Hz, 2H), 7.66 (d, J=8.78Hz, 2H), 7.34-7.40 (m, 2H), 7.31 (s, 2H), 7.18-7.27 (m, 2H), 6.97-7.05(m, 2H), 6.91 (dd, J=8.78, 2.26 Hz, 1H), 5.18 (m, 3H), 2.92 (s, 3H),1.60-1.68 (m, 2H), 1.45-1.55 (m, 2H), 1.32 (s, 6H), 1.18 (s, 6H).

Preparation 10 Intermediate 5-2 Synthesis of7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethyl-piperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yltrifluoromethanesulfonate

To a reaction mixture of7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(Intermediate 5-1, 3 g, 6.04 mmol) in DCM (30 mL) was added Et₃N (2.10mL, 15.10 mmol), and N-phenyltrifluoromethanesulfonimide (2.158 g, 6.04mmol) in two portions. The mixture was stirred at RT for 3 h and thenconcentrated in vacuo. The residue was loaded onto two 10 g SCX columns,washed with MeOH, and eluted with 2 M NH₃ in MeOH. Theproduct-containing fractions were concentrated to give Intermediate 5-2as a pale solid (3.47 g, 91% yield). MS (M+1)=629.5.

Preparation 11 Intermediate 5-3 Synthesis of7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yltrifluoromethanesulfonate

To a mixture of Intermediate 5-2 (500 mg, 0.795 mmol) in DCM (4 mL) wasadded BBr₃ (1 M solution in DCM, 2.4 mL, 2.4 mmol) slowly at −78° C. Themixture was stirred at −78° C. for 10 minutes, then warmed to RT andstirred for 1.5 hours. The reaction was quenched with MeOH andconcentrated. The residue was loaded onto an SCX column, washed withMeOH, eluted with 2 M NH₃ in MeOH. The product-containing fractions wereconcentrated to give Intermediate 5-3 as a light yellow solid (382 mg,89% yield). MS (M+1)=539.3.

Preparation 12 Intermediate 5-4 Synthesis of6-(3-(benzyloxy)-6-methoxynaphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a reaction mixture of7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(Intermediate 5-1, 500 mg, 1.01 mmol) in DMF (3 mL) was added 60% wt NaH(48.3 mg, 1.21 mmol) at 0° C. The mixture was stirred for 0.5 h, thenmethyl iodide (0.063 mL, 1.01 mmol) was added. The mixture was stirredat RT for 1.5 hours, then another portion of methyl iodide (0.063 mL,1.01 mmol) was added. The reaction mixture was stirred at RT overnight,then slowly quenched with water. The residue was partitioned betweenwater and DCM, and the aqueous layer was further extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, and concentrated invacuo. The residue was purified via silica gel flash columnchromotagraphy (0-20% 1.5 M NH₃ in MeOH/DCM) to give a mixture ofIntermediate 5-4 and6-(3-(benzyloxy)-6-methoxynaphthalen-2-yl)-N-methyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-aminewhich was used without further purification (412 mg, 80% yield). MS(M+1)=511.5.

Preparation 13 Intermediate 6-1 Synthesis of3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyltrifluoromethanesulfonate

Step 1:6-(4-(Benzyloxy)-2-(trifluoromethoxy)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

(4-(Benzyloxy)-2-(trifluoromethoxy)phenyl)boronic acid (1.2 g, 61% pure,2.307 mmol) and Intermediate 1-1 (246 mg, 0.871 mmol) were reactedaccording to GENERAL METHOD 1-5 for Suzuki coupling. Compound6-(4-(benzyloxy)-2-(trifluoromethoxy)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-aminewas obtained as a beige solid (405 mg, 90% yield) after flash columnchromatography purification. MS (M+1)=515.5.

Step 2:4-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenol

From compound6-(4-(benzyloxy)-2-(trifluoromethoxy)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(405 mg, 0.787 mmol), following GENERAL METHOD 4-1 for hydrogenolysis ofthe benzyl group, compound4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3(trifluoromethoxy)phenolwas obtained (335 mg, 100% yield) after SCX column purification. MS(M+1)=425.3.

Step 3:4-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenyltrifluoromethanesulfonate

To a suspension of4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenol(360 mg, 0.848 mmol) in DCM (5 mL) was added Et₃N (0.296 ml, 2.120 mmol)and N-phenyltrifluoromethanesulfonimide (364 mg, 1.018 mmol). Themixture was stirred at RT overnight. The reaction mixture wasconcentrated. The residue was loaded onto a 5 g SCX column, washed withMeOH, eluted with 2 M NH₃ in MeOH. The product-containing fractions wereconcentrated, and the crude product was purified via flash columnchromatography to give4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenyltrifluoromethanesulfonate as a beige solid (361 mg, 76%). MS (M+1)=557.5

Step 4:3-Hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyltrifluoromethanesulfonate

A mixture of4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenyltrifluoromethanesulfonate (360 mg, 0.647 mmol), iodobenzene diacetate(375 mg, 1.164 mmol) and Pd(OAc)₂ (7.3 mg, 0.032 mmol) in AcOH (3.0 mL)and Ac₂O (3.0 mL) was heated at 60° C. overnight. The reaction mixturewas cooled to room temperature and concentrated. The residue wasbasified with aqueous NaHCO₃ solution and extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, and concentrated. Thecrude material was loaded onto a SCX column, washed with MeOH anddiluted with 2 M NH₃ in MeOH. The product-containing fractions wereconcentrated. Compound3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyltrifluoromethanesulfonate was obtained as a yellow solid (110 mg, 28%)after flash column chromatography and HPLC purification. MS (M+1)=573.2.

Preparation 14 Intermediate 6-2 Synthesis of3-hydroxy-5-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate

Step 1: 3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

To a 500 mL pressure vessel was added 4-bromo-3-methoxyphenol (8.12 g,40 mmol), bis(pinacolato) diboron (22.4 g, 88.0 mmol), potassium acetate(27.4 g, 280 mmol), dppf (2.22 g, 4.00 mmol) and Pd(dppf)Cl₂ (2.93 g,4.00 mmol). Dioxane (120 mL) was added and the reaction mixture waspurged with nitrogen for 25 minutes. The reaction mixture was thensealed and stirred at 85° C. for 20 h. The mixture was diluted withethyl acetate, filtered through celite, and concentrated to a dark brownliquid. The liquid was passed through a plug of silica gel (60 g)eluting with heptane/ethyl acetate to provide3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol as awhite solid (4.0 g). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.60 (d, J=8.1Hz, 1H), 6.42 (dd, J=8.1, 2.0 Hz, 1H), 6.33 (d, J=2.0 Hz, 1H), 3.64 (s,3H), 1.35 (s, 12H).

Step 2:3-Methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

To a 25 mL microwave vial was added3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.90 g,10.8 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 2.55 g, 9.00 mmol), NaHCO₃ (2.27 g, 27.0 mmol) andtetrakis(triphenylphosphine) palladium(0) (0.520 g, 0.450 mmol). Dioxane(45 mL) and water (15 mL) were added, and the reaction mixture waspurged with nitrogen for 10 minutes. The reaction mixture was heatedunder microwave irradiation at 110° C. for 16 h. After cooling to RT,the mixture was filtered through celite, washing the filter padsequentially with ethyl acetate, DCM, and MeOH. Concentration of thefiltrate afforded a brown solid which was purified by flashchromatography (80 g silica, 0-20% 2 M ammonia in MeOH gradient, in DCM)to provide3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(1.6 g). MS (M+1)=371.3.

Step 3:3-Methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate

N-Phenyltrifluoromethanesulfonimide (2.160 g, 6.05 mmol) was addedportionwise to a mixture of3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenoland triethylamine (1.5 mL, 11 mmol) cooled to 0° C. The mixture wasallowed to warm to RT and to stir for 2 h. An additional portion ofN-phenyltrifluoromethanesulfonimide (0.30 g, 0.86 mmol) was added andthe mixture stirred at RT overnight. The solution was diluted withsaturated aqueous NaHCO₃ solution and extracted with DCM (2×). Theextracts were concentrated and the residue was purified by flashchromatography (40 g silica, 0-25% MeOH gradient in DCM) to provide3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate (1.8 g). MS (M+1)=503.4. ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 7.85 (d, J=9.6 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.20(d, J=9.6 Hz, 1H), 7.17 (d, J=2.5 Hz, 1H), 7.12 (dd, J=8.3, 2.3 Hz, 1H),5.44-5.59 (m, 1H), 3.92 (s, 3H), 3.04 (s, 3H), 1.98 (m, J=8.1 Hz, 4H),1.65 (s, 6H), 1.53 (s, 6H).

Step 4:3-Hydroxy-5-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate

A mixture of3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate (2.6 g, 5.17 mmol), Pd(OAc)₂ (58 mg, 0.259mmol), and iodobenzene diacetate (2.33 g, 7.24 mmol) in 1:1 aceticacid/acetic anhydride (42 mL) was heated at 50° C. for 8 h. The mixturewas cooled to RT and concentrated under reduced pressure. Flashchromatography (10-100% EtOH in DCM, followed by 7:1 EtOH/7 N ammonia inMeOH elution) provided a mixture of the title compound and thecorresponding acetate(3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(((trifluoromethyl)sulfonyl)oxy)phenylacetate). After concentration, the mixture was taken up in methanol andheated at 70° C. for 4 h. The solvent was evaporated to provide3-hydroxy-5-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoro-methanesulfonate as a tan-colored solid (1.25 g). MS(M+1)=519.4. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.08 (d, J=10.1 Hz,1H), 7.23 (d, J=10.1 Hz, 1H), 6.57 (s, 2H), 5.16 (t, J=12.1 Hz, 1H),3.89 (s, 3H), 3.02 (s, 3H), 1.69-1.77 (m, 2H), 1.56-1.67 (m, 2H), 1.41(s, 6H), 1.27 (s, 6H).

Preparation 15 Intermediate 7-1 Synthesis of6-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one

Step 1:6-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one

Following GENERAL METHOD 2-1 for boronate ester formation using5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-one (1.0 mg, 4.15 mmol) affords6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one(1.16 g) MS [M+H⁺]=289.2.

Step 2:6-Methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one

Following GENERAL METHOD 1-4 for Suzuki coupling using6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one(300 mg, 1.06 mmol) and6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 611 mg, 2.12 mmol) affords6-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one(433 mg) MS [M+H⁺]=409.7.

Preparation 16 Intermediate 8-1 Synthesis of5-bromo-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Step 1:(2-Fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Intermediate 1-1 (2.83 g, 10.0 mmol), (2-fluoro-6-methoxyphenyl)boronicacid, and K₃PO₄ (5.52 g, 26.0 mmol) were added to a microwave vial. 2ndGeneration XPhos Precatalyst (0.32 g, 0.40 mmol) was then added to themixture followed by addition of 1:1 THF/water (50 mL). The reactionmixture was sealed and stirred at RT for 4 h then extracted with CH₂Cl₂(2×). The crude material was purified by catch and release usingSiliaBond Propylsulfonic Acid® (3 eq, MeOH as eluent and a 2 N ammoniasolution in MeOH to release the material). The solvent was concentratedin vacuo to afford the title compound as a brown gel (2.87 g, 77%).[M+H]: 373.4; ¹H NMR (400 MHz, DMSO) δ 7.43 (td, J=8.5, 7.0 Hz, 1H),7.36 (d, J=9.5 Hz, 1H), 7.08 (d, J=9.5 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H),6.92 (td, J=8.5, 1.0 Hz, 1H), 5.07 (bs, 1H), 3.74 (s, 3H), 3.31 (s, 3H),1.47-1.55 (m, 2H), 1.33-1.48 (m, 2H), 1.24 (s, 6H), 1.09 (s, 6H).

Step 2:6-(4-Bromo-2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

(2-Fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(1.83 g, 4.91 mmol), [Ir(COD)(OMe)]₂ (0.16 g, 0.24 mmol), dtbpy (0.13 g,0.24 mmol), and bis(pinacolato)diboron (1.87 g, 7.37 mmol) in dioxane(40 mL) were heated at 80° C. overnight. The volatiles were removedunder vacuum. EtOH (20 mL), H₂O (20 mL) and CuBr₂ (3.29 g, 14.7 mmol)were added. The mixture was heated at reflux overnight. The reactionmixture was cooled to RT and the volatiles were removed under vacuum. A7% aqueous solution of NH₄OH was added and the aqueous phase wasextracted with DCM (3×). The product was then purified by silica gelcolumn chromatography (1-10% gradient of 7 N ammonia in MeOH, in CH₂Cl₂)to give an inseparable mixture of the desired product(6-(4-bromo-2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine)and4-bromo-6-(2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(1.26 g). [M+H]: 451.3.

Step 3:5-Bromo-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

6-(4-Bromo-2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(0.81 g, 1.80 mmol) and pyridine hydrochloride (1.65 g, 14.3 mmol) wereheated to 190° C. for 45 min in a Biotage® Initiator microwave reactor.The reaction mixture was diluted in MeOH/DMSO, and purified via reversephase preparative HPLC (5 to 95% acetonitrile in water, 0.1%trifluoroacetic acid as modifier). The appropriate fractions containingproduct were free based by catch and release using SiliaBondPropylsulphonic Acid® (4 eq, methanol as eluent and a 2 N ammoniasolution in MeOH to release the material). The solvent was concentratedin vacuo to afford5-bromo-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenolas a beige solid (0.19 g, 23%). [M+H]: 439.2; ¹H NMR (400 MHz, MeOD) δ7.96 (d, J=10.0 Hz, 1H), 7.27 (d, J=10.0 Hz, 1H), 6.97 (t, J=2.0 Hz,1H), 6.89 (dd, J=11.5, 2.0 Hz, 1H), 5.07-5.35 (m, 1H), 3.02 (s, 3H),1.73 (dd, J=12.5, 3.5 Hz, 2H), 1.62 (t, J=12.5 Hz, 2H), 1.41 (s, 6H),1.27 (s, 6H).

Preparation 17 Intermediate 9-1 Synthesis of3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate

Step 1: (4-Bromo-3-methoxyphenoxy)(tert-butyl)dimethylsilane

To a 5 L round bottom flask fitted with an overhead stirrer,thermocouple and N₂ inlet, was added 4-bromo-3-methoxyphenol (254 g,1251 mmol), DCM (2500 mL) and DIPEA (437 mL, 2502 mmol). The reactionmixture was cooled in an ice bath, followed by addition oftert-butylchlorodimethylsilane (198 g, 1314 mmol). The reaction mixturewas stirred at RT overnight, and then diluted with water. The organiclayer was separated, dried over sodium sulfate, filtered andconcentrated to provide(4-bromo-3-methoxyphenoxy)(tert-butyl)dimethylsilane (472 g, 1250 mmol,100% yield). MS (M+1)=319.2.

Step 2:tert-Butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane

To a 500 mL round bottom flask containing(4-bromo-3-methoxyphenoxy)(tert-butyl)dimethylsilane (1.9 g, 6 mmol) anddioxane (60 mL), was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.05 g,12.00 mmol), potassium acetate (2.35 g, 24.00 mmol), dppf (0.333 g,0.600 mmol) and PdCl₂(dppf).CH₂Cl₂ adduct (0.49 g, 0.600 mmol). Thereaction was evacuated and filled with N₂ twice and then stirred at 90°C. overnight. The reaction was then diluted with MeOH, filtered throughcelite and washed with EtOAc. After concentration in vacuo, the residuewas purified by silica gel chromatography using EtOAc/Heptane (0-15%) toprovide white solidtert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane(1.6 g, 4.17 mmol, 70% yield), MS (M+1)=365.2.

Step 3:3-Methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

A 20 L jacketed reactor fitted with a reflux condenser, N₂ inlet,thermocouple and overhead stirrer was charged with 2.7 L of dioxanefollowed bytert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane(290 g, 557 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 113 g, 398 mmol), and sodium bicarbonate (100 g, 1194mmol). 700 mL of water was added, followed by addition of Pd(PPh₃)₄(27.6 g, 23.88 mmol). The reaction mixture was heated at 72° C.overnight. After cooling to RT, the layers were separated. The organiclayer was concentrated, and the reside was purified by silica gelchromatography using 5% MeOH (containing 1% TEA) in DCM to provide thedesired product,3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(83 g, 211 mmol, 53% yield). MS=371.4.

Step 4:3-Methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate

A mixture of3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(1.6 g, 4.32 mmol) and Et₃N (1.50 mL, 10.8 mmol) in DCM (40 mL) wascooled in an ice-water bath, and N-phenyltrifluoromethanesulfonimide(2.16 g, 6.05 mmol) was added dropwise. After stirring at RT for 2 h,another 0.2 eq of N-phenyltrifluoromethanesulfonimide was added, and thereaction was stirred overnight. The reaction was quenched with anaqueous sodium bicarbonate solution and extracted with DCM. The organiclayer was washed with brine, separated and concentrated, and the residuewas purified by chromatography column using MeOH/DCM (0-25%) to provideIntermediate9-1,3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate (1.8 g, 3.58 mmol, 83% yield), MS=503.2.

Preparation 18 Intermediate 9-2 Synthesis of3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate

A 1 L round bottom flask fitted with a magnetic stir bar and N₂ inlet,was cooled in an ice-water bath, and3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate (37.00 g, 68.6 mmol) and DCM (360 mL) wereadded. Boron tribromide (1 M in DCM, 120 mL) was added slowly via asyringe. After stirring at RT for 4 h, the reaction was quenched withmethanol, and stirred at RT for 15 minutes. The reaction mixture wasconcentrated to provide a sticky glassy solid, which was refluxed in 1MHCl in MeOH (360 mL) overnight. After cooling to RT, the material wasconcentrated, and the residue was stirred in 4 N HCl in dioxane (18 mL)overnight. Filtration afforded the HCl salt of the desire product,3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate Intermediate 9-2 (36 g, 68.6 mmol, >100%yield), MS (M+1)=489.3. ¹H NMR (DMSO-d6) δ 9.06 (d, J=11.6 Hz, 1H), 8.28(d, J=10.1 Hz, 1H), 8.13 (d, J=12.1 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H),7.70 (d, J=9.1 Hz, 1H), 7.08-7.12 (m, 1H), 4.99 (br. s., 1H), 3.03 (s,3H), 2.03 (t, J=12.9 Hz, 2H), 1.80 (d, J=10.6 Hz, 2H), 1.54 (s, 6H),1.48 (s, 6H).

Preparation 19 Intermediate 9-3 Synthesis of6-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a microwave vial was added3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate (Intermediate 9-1, 4.0 g, 7.96 mmol),bis(pinacolato)diboron (4.45 g, 17.51 mmol), potassium acetate (4.69 g,47.8), PdCl₂(dppf).CH₂Cl₂ (0.65 g, 0.79 mmol), dppf (0.44 g, 0.79 mmol),and 1,4-dioxane (10 mL). The reaction solution was purged with nitrogen(3×) and stirred at 90° C. overnight. The reaction mixture was filteredthrough celite and the filter cake was washed with EtOAc. The filtratewas concentrated in vacuo to give a brown liquid which was purified bysilica gel chromotography (10%-60% EtOAc/Heptane) to afford6-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(1.6 g, MS: 481.5 [M+H⁺]).

General Method 1-5

Representative Procedure for Suzuki Coupling

Chloropyridazine intermediate, such as Intermediate 1-1, (1 equivalent),boronic acid reagent (1.2-1.5 equivalents), Pd(PPh₃)₄ (0.1 equivalents)and Na₂CO₃ or NaHCO₃ (2.5-3 equivalents) were added to a microwave vialfollowed by addition of 1,4-dioxane and H₂O (4:1). The reaction mixturewas sealed, then evacuated and filled with N₂ (4×) and heated viamicrowave irradiation at 120° C. for 1 h. The reaction mixture wasfiltered through celite and washed with EtOAc or 10% MeOH/DCM. Theresulting filtrate was concentrated and acidified to pH 3 using 1 M HClaqueous solution, then loaded on a SCX column, washed with MeOH, andeluted with 2 M NH₃ in MeOH. The product-containing fractions wereconcentrated and purified via flash column chromatography to afford thedesired product.

General Method 1-6

Representative Procedure for the Suzuki Coupling

Halo-pyridazine substrate (1 equivalent), boronic acid or ester reagent(2.5 equivalents), and Na₂CO₃ (3 equivalents) were added to a microwavevial. Pd(PPh₃)₄ (0.1 equivalents) was then added to the reaction mixturefollowed by addition of dioxane/water (6/1, 0.1 M). The reaction mixturewas sealed and heated in a Biotage® Initiator microwave reactor 130° C.for 1 h. The reaction mixture was filtered through celite and the filtercake was washed with methanol. The filtrate was concentrated in vacuoand the crude product was purified via reverse phase preparative HPLC(0.1% trifluoroacetic acid as modifier). The appropriate fractionscontaining product were free based by catch and release using SiliaBondPropylsulphonic Acid® (4 eq, methanol as eluent and a 2 N ammoniasolution in MeOH to release the material). The solvent was concentratedin vacuo and the resulting solid was suspended or dissolved in CH₃CN/H₂O(3/1 mL). 1 M aqueous HCl (3 equivalents) was added and the solvent wasconcentrated in vacuo to afford the desired compound as thehydrochloride salt.

General Method 7-1

Representative Procedure for Borylation/Bromination

A mixture of a 2,6-substituted phenylpyridazine intermediate, such as6-(2,6-dimethoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(1 equivalent), bis(pinacolato)diboron (1.5 equivalents),4,4′-di-tert-butyl bipyridine (dtbpy) (0.2 equivalents) and[Ir(COD)(OMe)]₂ (0.2 equivalents) in 1,4-dioxane was evacuated thenfilled with N₂ (4×), then heated at 90° C. overnight. The reactionmixture was cooled to RT and concentrated. To the residue was addedCuBr₂ (3 equivalents), MeOH and water (1:1). The mixture was heated at85° C. overnight, then cooled to RT, diluted with EtOAc, filteredthrough celite and washed with EtOAc. The filtrate was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified via flash column chromatography (MeOH/DCM) to afford thedesired product.

Example 24-1 Synthesis of7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2-naphthonitrile

A degassed mixture of7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yltrifluoromethanesulfonate (21 mg, 0.033 mmol), zinc cyanide (5.00 mg,0.043 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.8 mg, 1.6μmol) in DMF (0.8 mL) was heated at 120° C. under microwave irradiationfor 1 h. The reaction mixture was filtered through celite, washed withEtOAc and concentrated. The residue was loaded on a 1 g SCX column,washed with MeOH, and eluted with 2 M NH₃ in MeOH. Theproduct-containing fractions were concentrated. The crude product waspurified via HPLC to give the title compound as a light yellow solid(6.9 mg, 50% yield). LCMS Rt=0.55 min [Method Q], MS (M+1)=416.3. ¹H NMR(METHANOL-d₄) δ 8.26 (s, 1H), 8.16 (d, J=9.6 Hz, 1H), 8.04 (s, 1H), 7.86(d, J=8.6 Hz, 1H), 7.32 (dd, J=8.6, 1.5 Hz, 1H), 7.27 (s, 1H), 7.22 (d,J=9.6 Hz, 1H), 5.05 (t, J=11.9 Hz, 1H), 2.94 (s, 3H), 1.61 (dd, J=13.1,3.5 Hz, 2H), 1.49 (t, J=12.4 Hz, 2H), 1.30 (s, 6H), 1.14 (s, 6H).

Example 24-2 Synthesis of3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(piperidin-1-ylmethyl)naphthalen-2-ol

Step 1:6-(3-(Benzyloxy)-6-(piperidin-1-ylmethyl)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

A degassed reaction mixture of Intermediate 5-2 (125 mg, 0.199 mmol),potassium-1-trifluoroboratomethylpiperidine (44.8 mg, 0.219 mmol),palladium acetate (2.2 mg, 9.9 μmol), X-Phos (9.5 mg, 0.020 mmol) andCs₂CO₃ (194 mg, 0.596 mmol) in THF (1 mL) and water (0.1 mL) was heatedat 80° C. for 25 h. The reaction mixture was filtered through celite andwashed with EtOAc. The filtrate was concentrated and acidified to pH 3by addition of 1 M aqueous HCl. The residue was loaded onto an SCXcolumn, washed with MeOH and eluted with 2 M NH₃ in MeOH. Theproduct-containing fractions were concentrated and the crude product waspurified via HPLC to give the title compound (34 mg). MS (M+1)=578.7.

Step 2:3-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(piperidin-1-ylmethyl)naphthalen-2-ol

A H₂ purged mixture of6-(3-(benzyloxy)-6-(piperidin-1-ylmethyl)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(34 mg, 0.059 mmol) and 10% wt Pd/C (0.3 mg, 3 μmol) in MeOH (3 mL) andEtOAc (3 mL) was stirred under a H₂ atmosphere at RT overnight. Thereaction mixture was filtered through celite, rinsed with MeOH andconcentrated. The crude material was purified via HPLC to give thedesired product as a yellow solid (15 mg, 52.3% yield). LCMS Rt=0.45 min[Method Q], MS (M−1)=486.4. ¹H NMR (METHANOL-d₄) δ 8.16 (s, 1H), 8.12(d, J=10.1 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.46 (s, 1H), 7.15-7.22 (m,2H), 7.14 (s, 1H), 4.98 (t, J=12.1 Hz, 1H), 3.49 (s, 2H), 2.89 (s, 3H),2.37 (br. s., 4H), 1.34-1.60 (m, 10H), 1.29 (s, 6H), 1.13 (s, 6H).

Example 24-3 Synthesis of3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(pyrrolidin-1-ylmethyl)naphthalen-2-ol

A degassed reaction mixture of Intermediate 5-3 (50 mg, 0.093 mmol),potassium-1-trifluoroboratomethylpyrrolidine (26.6 mg, 0.139 mmol),palladium acetate (1.0 mg, 4.6 μmol), X-phos (4.4 mg, 9.3 μmol) andCs₂CO₃ (91 mg, 0.28 mmol) in THF (1 mL) and water (0.1 mL) was heated at100° C. for 1 h under microwave irradiation. The reaction mixture wasconcentrated, acidified to pH 3 by addition of 1 M aqueous HCl andloaded onto an SCX column, then washed with MeOH, and eluted with 2 MNH₃ in MeOH. The product-containing fractions were concentrated and thecrude material was purified via HPLC to give the desired product as awhite solid (6 mg, 13% yield). MS (M+1)=473.32. ¹H NMR (METHANOL-d₄) δ8.29 (s, 1H), 8.26 (d, J=10.1 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.60 (s,1H), 7.29-7.36 (m, 2H), 7.25 (s, 1H), 5.11 (t, J=12.4 Hz, 1H), 3.76 (s,2H), 3.01 (s, 3H), 2.56-2.67 (m, 4H), 1.77-1.89 (m, 4H), 1.65-1.74 (m,2H), 1.52-1.63 (m, 2H), 1.39 (s, 6H), 1.23 (s, 6H).

Example 24-4 Synthesis of1-bromo-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol

Step 1:7-(Benzyloxy)-1-bromo-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

To a mixture of7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(100 mg, 0.201 mmol) in DMF (1 mL) was added N-bromosuccinimide (39.4mg, 0.221 mmol) at 0° C. The reaction mixture was stirred at RT for 1.5h, then loaded onto a 2 g SCX column, washed with MeOH, and eluted with2M NH₃ in MeOH. The product-containing fractions were concentrated andthe crude material was purified via silica gel flash columnchromatography to give the desired product as a brown solid (33.6 mg,29% yield). MS (M+1)=577.3.

Step 2:3-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(piperidin-1-ylmethyl)naphthalen-2-ol

To a mixture of7-(benzyloxy)-1-bromo-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(29 mg, 0.050 mmol) in DCM (1 mL) was added BBr₃ (1 M solution in DCM,0.25 mL, 0.25 mmol) slowly at −78° C. The mixture was stirred at −78° C.for 10 minutes, then warmed to room temperature and stirred at for 2 h.The reaction was quenched with MeOH and concentrated. The residue wasloaded onto a 1 g SCX column, washed with MeOH and eluted with 2 M NH₃in MeOH. The product-containing fractions were concentrated to give thedesired product as a light brown solid (14 mg, 57% yield). LCMS Rt=0.54min [Method Q], MS (M+1)=487.2. ¹H NMR (METHANOL-d₄) δ 8.18-8.29 (m,2H), 7.70 (d, J=8.6 Hz, 1H), 7.50 (s, 1H), 7.33 (d, J=10.1 Hz, 1H), 6.99(d, J=8.6 Hz, 1H), 5.16 (t, J=11.9 Hz, 1H), 3.03 (s, 3H), 1.72-1.80 (m,2H), 1.61-1.70 (m, 2H), 1.45 (s, 6H), 1.29 (s, 6H).

Example 24-5 Synthesis of1-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol

Step 1:7-(Benzyloxy)-1-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

To a reaction mixture of7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(100 mg, 0.201 mmol) in DMF (2 mL) was added N-chlorosuccinimide (32.3mg, 0.242 mmol) at room temperature. The reaction mixture was stirredovernight then loaded onto an SCX column, washed with MeOH, and elutedwith 2 M NH₃ in MeOH. The product-containing fractions were concentratedand purified via silica gel flash column chromatography to give thetitle compound as a light brown solid product (25 mg, 23% yield). MS(M+1)=531.6.

Step 2:1-Chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol

To a mixture of7-(benzyloxy)-1-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(25 mg, 0.047 mmol) in DCM (1 mL) was added BBr₃ (1 M solution in DCM,0.25 mL, 0.25 mmol) slowly at −78° C. The mixture was stirred at −78° C.for 10 minutes, then warmed to RT and stirred for 1.5 h. The reactionwas quenched with MeOH and concentrated. The residue was loaded onto a 1g SCX column, washed with MeOH and eluted with 2 M NH₃ in MeOH. Theproduct-containing fractions were concentrated to give the desiredproduct as a light brown solid (10 mg, 48.2% yield). LCMS Rt=0.54 min[Method Q], MS (M+1)=441.3. ¹H NMR (METHANOL-d₄) δ 8.17-8.27 (m, 2H),7.66 (d, J=9.1 Hz, 1H), 7.46 (s, 1H), 7.32 (d, J=10.1 Hz, 1H), 7.00 (d,J=9.1 Hz, 1H), 5.13 (t, J=11.9 Hz, 1H), 3.02 (s, 3H), 1.71-1.79 (m, 2H),1.59-1.68 (m, 2H), 1.44 (s, 6H), 1.28 (s, 6H).

Example 24-6 Synthesis of7-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

Following GENERAL METHOD 4-1 for hydrogenolysis of the benzyl group,7-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-olwas prepared from Intermediate 5-4 (70 mg, 0.14 mmol). A white solid wasobtained after HPLC purification (30 mg, 52% yield). LCMS Rt=0.57 min[Method Q], MS (M+1)=421.3. ¹H NMR (METHANOL-d₄) δ 8.25 (d, J=9.6 Hz,1H), 8.22 (s, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.33 (d, J=9.6 Hz, 1H), 7.19(s, 1H), 7.05 (d, J=2.5 Hz, 1H), 6.93 (dd, J=8.6, 2.5 Hz, 1H), 5.10 (t,J=12.1 Hz, 1H), 3.90 (s, 3H), 3.02 (s, 3H), 1.68-1.76 (m, 2H), 1.55-1.65(m, 2H), 1.41 (s, 6H), 1.25 (s, 6H).

Example 24-7 Synthesis of7-methoxy-3-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

Step 1:6-(3-(Benzyloxy)-6-methoxynaphthalen-2-yl)-N-methyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine

To a mixture of Intermediate 5-4 (400 mg, 0.783 mmol) in DMSO (1.5 mL)and water (3 mL) was added 37% wt formaldehyde (0.087 mL, 1.2 mmol) andformic acid (0.060 mL, 1.6 mmol). The mixture was heated at 120° C.under microwave irradiation for 20 mins. The mixture was heated at 120°C. under microwave irradiation for 20 minutes two more times afteraddition of additional portions of formaldehyde (0.087 mL, 1.28 mmol)and formic acid (0.060 ml, 1.6 mmol) each time. The reaction mixture wasconcentrated and loaded onto a 5 g SCX column, washed with MeOH, andeluted with 2 M NH₃ in MeOH. The product-containing fractions wereconcentrated and the crude product was purified by flash columnchromotagraphy (0-20% 1.5 M NH₃ in MeOH/DCM) to give the desired productas beige solid (340 mg, 83% yield). MS (M+1)=525.6.

Step 2:7-Methoxy-3-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

From compound6-(3-(benzyloxy)-6-methoxynaphthalen-2-yl)-N-methyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine(200 mg, 0.381 mmol), following GENERAL METHOD 4-1 for hydrogenolysis ofthe benzyl group, compound7-methoxy-3-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-olwas obtained as a beige solid (150 mg, 91% yield) after flash columnchromotagraphy (0-15% 1.5 M of NH₃ in MeOH/DCM) purification. Theproduct was converted to the HCl salt by addition of 4 M aqueous HCl(0.2 mL, 2.3 equivalents), followed by lyophilization. LCMS Rt=0.53 min[Method Q], MS (M+1)=435.3. ¹H NMR (METHANOL-d₄) δ 8.52 (d, J=10.1 Hz,1H), 8.18 (s, 1H), 8.02 (d, J=9.6 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.30(s, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.04 (dd, J=9.1, 2.5 Hz, 1H), 5.06 (t,J=11.4 Hz, 1H), 3.93 (s, 3H), 3.20 (s, 3H), 2.90 (s, 3H), 2.38 (t,J=13.1 Hz, 2H), 2.11 (dd, J=13.6, 3.0 Hz, 2H), 1.63 (s, 6H), 1.62 (s,6H).

Example 24-8 Synthesis of7-(3,6-dihydro-2H-pyran-4-yl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

A degassed reaction mixture of Intermediate 5-3 (100 mg, 0.186 mmol),3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (50.7 mg, 0.241 mmol),and tetrakis(triphenylphosphine)palladium(0) (10.73 mg, 9.28 μmol) in1,4-dioxane (2 mL) and 1 M aq. Na₂CO₃ solution (0.46 mL, 0.464 mmol)were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. Thecrude product was purified by HPLC to give the title compound as a lightbrown solid (65 mg, 73% yield). LCMS Rt=0.60 min [Method Q], MS(M+1)=473.4. ¹H NMR (METHANOL-d₄) δ 8.20-8.40 (m, 2H), 7.81 (d, J=8.6Hz, 1H), 7.67 (s, 1H), 7.48 (dd, J=8.8, 1.8 Hz, 1H), 7.35 (d, J=10.1 Hz,1H), 7.29 (s, 1H), 6.37 (br. s., 1H), 5.13 (t, J=12.0 Hz, 1H), 4.37 (d,J=2.5 Hz, 2H), 3.99 (t, J=5.6 Hz, 2H), 3.04 (s, 3H), 2.67 (s, 2H),1.68-1.78 (m, 2H), 1.55-1.66 (m, 2H), 1.41 (s, 6H), 1.25 (s, 6H).

Example 24-9 Synthesis of3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)naphthalen-2-ol

From compound7-(3,6-dihydro-2H-pyran-4-yl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(200 mg, 0.381 mmol), following GENERAL METHOD 4-1, compound3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)naphthalen-2-olwas obtained as a white solid after HPLC purification (11 mg, 24%yield). LCMS Rt=0.59 min [Method Q], MS (M+1)=475.4. ¹H NMR(METHANOL-d₄) δ 8.25-8.32 (m, 2H), 7.81 (d, J=8.6 Hz, 1H), 7.52 (s, 1H),7.35 (d, J=10.1 Hz, 1H), 7.19-7.27 (m, 2H), 5.12 (t, J=12.9 Hz, 1H),4.09 (dd, J=10.6, 3.0 Hz, 2H), 3.62 (td, J=11.2, 3.3 Hz, 2H), 3.04 (s,3H), 2.94 (dt, J=10.5, 5.6 Hz, 1H), 1.81-1.97 (m, 4H), 1.68-1.76 (m,2H), 1.55-1.65 (m, 2H), 1.41 (s, 6H), 1.25 (s, 6H).

Example 24-10 Synthesis of7-(difluoromethyl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

Step 1:6-(3-(Benzyloxy)-6-vinylnaphthalen-2-yl)-N-methyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine

Vinylboronic acid pinacol ester (100 mg, 0.651 mmol) and Intermediate5-2 (315 mg, 0.501 mmol) were reacted according to GENERAL METHOD 1-5for Suzuki coupling. A beige solid (250 mg, 98% yield) was obtainedafter SCX purification. The crude material was carried on withoutfurther purification. MS (M+1)=507.5.

Step 2:7-(Benzyloxy)-6-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)-2-naphthaldehyde

To a mixture of6-(3-(benzyloxy)-6-vinylnaphthalen-2-yl)-N-methyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine(106 mg, 0.209 mmol) and osmium tetroxide (4% wt aqueous solution, 0.080mL, 0.013 mmol) in 5:1 THF/water (60 mL) was added sodium periodate (112mg, 0.523 mmol) at RT. The mixture was stirred at RT overnight and thenquenched with 20% Na₂S₂O₃ aqueous solution. The crude mixture wasbasified with aqueous NaHCO₃ solution and extracted with DCM. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was loaded onto a 2 g SCX column, washed with MeOH, eluted with2 M NH₃ in MeOH. The product-containing fractions were concentrated togive 75 mg of a beige solid which was comprised of a 1:1 mixture of thetitle compound and the corresponding dimethyl acetal. This mixture wasdissolved into DCM (1.5 mL) and TFA (0.22 mL) and stirred at RT for 2 h.The mixture was concentrated, basified with NaHCO₃ aqueous solution andextracted with DCM. The organic layer was dried over Na₂SO₄, filteredand concentrated to give7-(benzyloxy)-6-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)-2-naphthaldehydeas a light brown solid. The crude material was carried on withoutfurther purification. MS (M+1)=509.4.

Step 3:6-(3-(Benzyloxy)-6-(difluoromethyl)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a mixture of7-(benzyloxy)-6-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)-2-naphthaldehyde(75 mg, 0.147 mmol) in DCM (1.5 mL) was added diethylaminosulfurtrifluoride (DAST) (0.058 mL, 0.44 mmol) at 0° C. The mixture wasstirred at 0° C. for 10 minutes then warmed to RT and stirred for 2days. The reaction mixture was quenched with aqueous NaHCO₃ at 0° C. andextracted with DCM. The organic layer was dried over Na₂SO₄, filteredand concentrated. The crude product was purified by HPLC to give thetitle compound as white solid (20.6 mg, 26% yield). MS (M+1)=531.1.

Step 4:7-(Difluoromethyl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

From compound6-(3-(benzyloxy)-6-(difluoromethyl)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(15 mg, 0.028 mmol), following GENERAL METHOD 4-1 for hydrogenolysis ofthe benzyl group, compound7-(difluoromethyl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-olwas obtained after HPLC purification (6 mg, 50% yield). LCMS Rt=0.60 min[Method Q], MS (M+1)=441.3. ¹H NMR (METHANOL-d₄ δ 8.37 (s, 1H), 8.29 (d,J=9.6 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.85 (s, 1H), 7.41 (d, J=8.6 Hz,1H), 7.37 (s, 1H), 7.34 (d, J=9.6 Hz, 1H), 6.87 (t, J=58.0 Hz, 1H), 5.23(t, J=12.1 Hz, 1H), 3.03 (s, 3H), 1.74-1.83 (m, 2H), 1.64-1.74 (m, 2H),1.47 (s, 6H), 1.28-1.37 (m, 6H).

Example 24-11 and 24-12 Synthesis of7-((4-hydroxy-2-methylbutan-2-yl)oxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-oland7-(3-hydroxy-3-methylbutoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol

Step 1:3-((7-(Benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yl)oxy)-3-methylbutan-1-oland4-((7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-yl)oxy)-2-methylbutan-2-ol

To a 50 mL round bottom flask was added7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(Example 20-2, Step 1, 640 mg, 1.289 mmol) and 3-methylbutane-1,3-diol(550 μL, 5.15 mmol) in THF (8.6 mL) to give a tan solution.Triphenylphosphine (744 mg, 2.84 mmol) and DIAD (560 μl, 2.71 mmol) wereadded, and the mixture was stirred under nitrogen at room temperature.After stirring overnight, the reaction was concentrated to dryness, thenwater and EtOAc were added, and the organic layer was separated. Theorganic layer was extracted with 0.2 N HCl, then sat. NaHCO₃ was addedto neutralize the aqueous layer, which was then extracted with EtOAc(2×). The combined organics were dried over MgSO₄, filtered, andconcentrated in vacuo. The crude material (a ˜1:1 mixture ofregioisomers) was taken on to next step without further purification.

Step 2

7-((4-Hydroxy-2-methylbutan-2-yl)oxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(43 mg, 0.097 mmol, 12% yield, 2 steps) and7-(3-hydroxy-3-methylbutoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol(29 mg, 0.058 mmol, 9% yield, 2 steps) were prepared from the benzyladducts following GENERAL METHOD 4-1 for hydrogenolysis. Purificationand separation by preparative HPLC (Waters Sunfire 30 mm ID×50 mm, 0.1%TFA, 25-50% ACN/H₂O) provided the regioisomeric products.

7-((4-Hydroxy-2-methylbutan-2-yl)oxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol:LCMS Rt=0.52 min [Method Q], M+1=493.4. ¹H NMR (400 MHz, CHLOROFORM-d) δ8.04 (s, 1H), 8.00 (d, J=10.04 Hz, 1H), 7.68 (d, J=9.03 Hz, 1H), 7.29(s, 1H), 7.23-7.27 (m, 2H), 7.04 (d, J=10.04 Hz, 1H), 6.98 (dd, J=2.26,8.78 Hz, 1H), 4.98 (br. s., 1H), 4.00 (t, J=5.90 Hz, 2H), 3.49 (s, 2H),3.04 (s, 3H), 2.04 (t, J=5.90 Hz, 2H), 1.73 (dd, J=3.39, 12.42 Hz, 2H),1.40-1.47 (m, 8H), 1.38 (s, 6H), 1.21 (s, 6H).

7-(3-Hydroxy-3-methylbutoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol:LCMS Rt=0.54 min [Method Q], M+1=493.4. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.95-8.03 (m, 2H), 7.66 (d, J=8.78 Hz, 1H), 7.28 (s, 1H), 7.26 (s, 1H),6.99-7.07 (m, 2H), 6.93 (dd, J=2.38, 8.91 Hz, 1H), 4.96 (br. s., 1H),4.31 (t, J=6.27 Hz, 2H), 3.04 (s, 3H), 2.07 (t, J=6.15 Hz, 2H), 1.72(dd, J=3.39, 12.42 Hz, 2H), 1.38 (m, 8H), 1.35 (s, 6H), 1.21 (s, 6H).

Example 25-1 Synthesis of2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)benzene-1,3-diol

Step 1:6-(2,6-Dimethoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Intermediate 1-1 (566 mg, 2.0 mmol) and 2,6-dimethoxyphenylboronic acid(437 mg, 2.4 mmol) were reacted according to GENERAL METHOD 1-5 forSuzuki coupling.6-(2,6-Dimethoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-aminewas obtained as a beige solid (375 mg, 49% yield) after flash columnchromotagraphy purification. MS (M+1)=385.4.

Step 2:6-(4-Bromo-2,6-dimethoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

6-(4-Bromo-2,6-dimethoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(240 mg, 0.624 mmol), bis(pinacolato)diboron (238 mg, 0.936 mmol),4.4′-di-tert-butyl-bipyridine(dtbpy, 3.4 mg, 0.012 mmol) and[Ir(COD)(OMe)]2 (4.1 mg, 6.2 μmol) were reacted following GENERAL METHOD7-1 for borylation/bromination, and6-(4-bromo-2,6-dimethoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-aminewas obtained as a yellow solid (176 mg, 60% yield) after flash columnchromotagraphy and HPLC purification. MS (M+1)=465.4.

Step 3:6-(2,6-Dimethoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

6-(4-Bromo-2,6-dimethoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(63 mg, 0.136 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (52.8 mg,0.272 mmol) were reacted according to GENERAL METHOD 1-5 for Suzukicoupling. The title compound was obtained as a yellow solid after columnchromatography (43 mg, 70% yield). MS (M+1)=451.5.

Step 4:2-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)benzene-1,3-diol

From compound6-(2,6-dimethoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(43 mg, 0.095 mmol), following GENERAL METHOD 3-1 for methoxydeprotection using thiophenol (22.1 mg, 0.2 mmol), compound2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)benzene-1,3-diolwas afforded as a pale yellow solid (20 mg, 45% yield) after HPLCpurification. LCMS Rt=0.41 min [Method Q], MS (M+1)=423.3. ¹H NMR(METHANOL-d₄) δ 8.60 (d, J=10.1 Hz, 1H), 7.91 (s, 2H), 7.20 (d, J=10.1Hz, 1H), 6.66 (s, 2H), 5.01 (t, J=12.4 Hz, 1H), 2.90-3.01 (m, 3H),1.64-1.73 (m, 2H), 1.52-1.61 (m, 2H), 1.38 (s, 6H), 1.23 (s, 6H).

Example 25-2 Synthesis of3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Step 1: 1-(Benzyloxy)-2-bromo-3-methoxybenzene

To a mixture of 3-(benzyloxy)-2-bromophenol (2.55 g, 9.14 mmol) in DMF(8 mL) was added K₂CO₃ (1.894 g, 13.70 mmol) and MeI (0.63 mL, 10.05mmol) at RT. The reaction mixture was stirred overnight then quenchedwith water and diluted with EtOAc. The organic phase was washed withwater (3×), brine, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by flash column chromatography (EtOAc/Heptane) toafford the title compound as a colorless oil (2.66 g, 99% yield). ¹H NMR(CHLOROFORM-d) δ 7.49 (d, J=7.1 Hz, 2H), 7.36-7.43 (m, 2H), 7.30-7.35(m, 1H), 7.20 (t, J=8.3 Hz, 1H), 6.56-6.65 (m, 2H), 5.18 (s, 2H), 3.92(s, 3H).

Step 2: (2-(Benzyloxy)-6-methoxyphenyl)boronic acid

To a mixture of 1-(benzyloxy)-2-bromo-3-methoxybenzene (2.66 g, 9.07mmol) in THF (20 mL) was added butyllithium (2.5 M in THF, 4 mL, 9.98mmol) at −78° C. dropwise over 15 minutes. The mixture was stirred at−78° C. for 30 minutes, then trimethylborate (4.0 mL, 36.3 mmol) wasadded. The mixture was allowed to warm to RT and stirred overnight. Themixture was quenched with 1 M aqueous HCl to pH 2 and extracted withDCM. The organic phase was dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash column chromatography (EtOAc/Heptane)to afford the desired product as a white solid (1.07 g, 46% yield). MS(M+1)=259.4.

Step 3:6-(2-(Benzyloxy)-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Intermediate 1-1 (391 mg, 1.384 mmol) and(2-(benzyloxy)-6-methoxyphenyl)boronic acid (500 mg, 1.94 mmol) werereacted according to GENERAL METHOD 1-5 for Suzuki coupling.6-(2-(Benzyloxy)-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-aminewas obtained as a beige solid (358 mg, 56% yield) after flash columnchromatography purification. MS (M+1)=461.5.

Step 4:6-(2-(Benzyloxy)-4-bromo-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

From compound6-(2-(benzyloxy)-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(300 mg, 0.651 mmol), following GENERAL METHOD 7-1 forborylation/bromination,6-(2-(benzyloxy)-4-bromo-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-aminewas obtained after flash column chromatography purification (170 mg, 50%pure, 24% yield). MS (M+1)=541.4.

Step 5:6-(2-(Benzyloxy)-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

6-(2-(Benzyloxy)-4-bromo-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(129 mg, 50% pure, 0.12 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (46.4 mg,0.24 mmol) were reacted according to GENERAL METHOD 1-5 for Suzukicoupling.6-(2-(Benzyloxy)-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-aminewas obtained as a yellow solid (14 mg, 22% yield) after HPLCpurification. MS (M+1)=527.4.

Step 6:3-Methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

From compound6-(2-(benzyloxy)-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(14 mg, 0.027 mmol), following GENERAL METHOD 4-1 for hydrogenolysis ofthe benzyl group, compound3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenolwas obtained after HPLC purification (4.2 mg, 35% yield). LCMS Rt=0.43min [Method Q], MS (M+1)=437.4. ¹H NMR (METHANOL-d₄) δ 8.23 (d, J=10.1Hz, 1H), 8.01 (br. s., 2H), 7.22 (d, J=10.1 Hz, 1H), 6.79-6.87 (m, 2H),5.13 (t, J=12.4 Hz, 1H), 3.94 (s, 3H), 3.00 (s, 3H), 1.72-1.82 (m, 2H),1.60-1.72 (m, 2H), 1.45 (s, 6H), 1.30 (s, 6H).

Example 25-3 Synthesis of5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenol

Step 1: 4-(Benzyloxy)-1-bromo-2-(trifluoromethoxy)benzene

To a mixture of 4-bromo-3-(trifluoromethoxy)phenol (2.97 g, 11.6 mmol)in DMF (10 mL) was added Cs₂CO₃ (5.65 g, 17.3 mmol) and benzyl chloride(1.46 mL, 12.7 mmol) at RT. The reaction mixture was stirred overnightthen quenched with water and diluted with EtOAc. The organic phase waswashed with water (3×), brine, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by flash column chromatography(EtOAc/Heptane) to afford the title compound as a colorless oil (3.92 g,98% yield). ¹H NMR (METHANOL-d₄) δ 7.51 (d, J=9.1 Hz, 1H), 7.40-7.45 (m,4H), 7.34-7.40 (m, 1H), 6.97 (dd, J=2.5, 1.5 Hz, 1H), 6.82 (dd, J=9.1,3.0 Hz, 1H), 5.06 (s, 2H).

Step 2: (4-(Benzyloxy)-2-(trifluoromethoxy)phenyl)boronic acid

To a mixture of 4-(benzyloxy)-1-bromo-2-(trifluoromethoxy)benzene (1.8g, 5.19 mmol) in THF (20 mL) was added butyllithium (2.5 M in THF, 2.28mL, 5.70 mmol) at −78° C. dropwise over 10 minutes. The reaction mixturewas stirred at −78° C. for 1 h, then trimethylborate (1.73 mL, 15.6mmol) was added. The mixture was warmed to room temperature and stirredovernight. The mixture was concentrated from diethyl ether three timesand the residue was dried on high vacuum to provide the title compoundas a gummy solid (2.2 g, 61% pure, 83% yield). The crude material wascarried on without further purification. MS (M−1)=311.3

Step 3:6-(4-(Benzyloxy)-2-(trifluoromethoxy)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

(4-(Benzyloxy)-2-(trifluoromethoxy)phenyl)boronic acid (360 mg, 61%pure, 0.692 mmol) and Intermediate 1-2 (93 mg, 0.346 mmol) were reactedaccording to GENERAL METHOD 1-5 for Suzuki coupling.6-(4-(Benzyloxy)-2-(trifluoromethoxy)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-aminewas obtained as a white solid (121 mg, 70% yield) after flash columnchromotagraphy purification. MS (M+1)=501.3.

Step 4:4-(6-((2,2,6,6-Tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenol

From compound6-(4-(benzyloxy)-2-(trifluoromethoxy)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(120 mg, 0.24 mmol), following GENERAL METHOD 4-1 for hydrogenolysis ofthe benzyl group,4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenolwas obtained after SCX column purification (98 mg, 100% yield). MS(M+1)=411.3.

Step 5:4-(6-((2,2,6,6-Tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenyltrifluoromethanesulfonate

To a suspension of4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenol(98 mg, 0.239 mmol) in DCM (2 mL) was added Et₃N (0.083 mL, 0.597 mmol)and N-phenyltrifluoromethanesulfonimide (172 mg, 0.48 mmol). DMF (0.5mL) was added to aid in dissolution. The solution was stirred at roomtemperature overnight then concentrated. The residue was loaded onto a 2g SCX column, washed with MeOH, eluted with 2 M NH₃ in MeOH. Theproduct-containing fractions were concentrated, and the crude materialwas purified via flash column chromatography to give the title compoundas a beige solid (89 mg, 69%). MS (M+1)=543.3.

Step 6:3-Hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyltrifluoromethanesulfonate

A mixture of4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenyltrifluoromethanesulfonate (86 mg, 0.16 mmol), iodobenzene diacetate(71.5 mg, 0.222 mmol) and Pd(OAc)₂ (3.6 mg, 0.016 mmol) in AcOH (0.6 mL)and Ac₂O (0.6 mL) was heated at 75° C. for 3 hours. The mixture was thenheated at 80° C. overnight after addition of another 40 mg ofiodobenzene diacetate. The reaction mixture was cooled to roomtemperature and concentrated. The residue was loaded onto an SCX column,washed with MeOH and diluted with 2 M NH₃ in MeOH. Theproduct-containing fractions were concentrated. The residue was treatedwith 7 M NH₃/MeOH and stirred at 40° C. for 4 h. The crude material waspurified via flash column chromatography to give the title compound as abeige solid (32 mg, 36.1%). MS (M+1)=559.4.

Step 7:5-(1H-Pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenol

3-Hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyltrifluoromethanesulfonate (32 mg, 0.043 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16.68 mg,0.086 mmol) were reacted according to GENERAL METHOD 1-5 for Suzukicoupling.5-(1H-Pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenolwas obtained as a yellow solid after HPLC purification. The product wasconverted to the HCl salt by addition of 1 M aqueous HCl (0.1 mL, 2.3equivalents) followed by lyophilization (10 mg, 45% yield). LCMS Rt=0.48min [Method Q], MS (M+1)=477.3. ¹H NMR (METHANOL-d₄) δ 8.17 (s, 2H),8.05 (d, J=9.6 Hz, 1H), 7.68 (d, J=9.6 Hz, 1H), 7.22-7.30 (m, 2H), 4.49(t, J=12.1 Hz, 1H), 2.33 (dd, J=13.6, 3.5 Hz, 2H), 1.70 (t, J=12.9 Hz,2H), 1.61 (s, 6H), 1.54 (s, 6H).

Example 25-4 Synthesis of2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenol

Intermediate 6-1 (40 mg, 0.070 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(29.1 mg, 0.140 mmol) were reacted according to GENERAL METHOD 1-5 forSuzuki coupling, and2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenolwas obtained as a white solid (7.5 mg, 21% yield). LCMS Rt=0.52 min[Method Q], MS (M+1)=505.4. ¹H NMR (METHANOL-d₄) δ 8.04 (s, 1H), 7.85(s, 1H), 7.79 (d, J=9.6 Hz, 1H), 7.25 (d, J=9.6 Hz, 1H), 7.11-7.17 (m,1H), 7.07 (d, J=1.5 Hz, 1H), 5.24 (t, J=11.4 Hz, 1H), 3.94 (s, 3H), 3.02(s, 3H), 1.72-1.82 (m, 2H), 1.60-1.72 (m, 2H), 1.44 (s, 6H), 1.29 (s,6H).

Example 25-5 Synthesis of2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenol

Intermediate 6-1 (35 mg, 0.061 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (23.72 mg,0.122 mmol) were reacted according to GENERAL METHOD 1-5 for Suzukicoupling, and2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenolwas obtained as a white solid (27 mg, 90% yield). LCMS Rt=0.50 min[Method Q], MS (M+1)=491.4. ¹H NMR (METHANOL-d₄) δ 8.02 (br. s., 2H),7.79 (d, J=9.6 Hz, 1H), 7.25 (d, J=9.6 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H),7.10-7.13 (m, 1H), 5.26 (t, J=11.9 Hz, 1H), 3.01 (s, 3H), 1.72-1.84 (m,2H), 1.61-1.72 (m, 2H), 1.45 (s, 6H), 1.30 (s, 6H).

Example 25-6 Synthesis of4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyl)-1-methylpyridin-2(1H)-one

Intermediate 6-1 (40 mg, 0.070 mmol) and 1-methylpyridin-2-one-4-boronicacid pinacol ester (32.8 mg, 0.140 mmol) were reacted according toGENERAL METHOD 1-5 for Suzuki coupling, and4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyl)-1-methylpyridin-2(1H)-onewas obtained as a white solid. The product was converted to the HCl saltby addition of 4 M HCl in dioxane (0.1 mL, 5.7 equivalents), followed byevaporation of the solvent (14.5 mg, 36% yield). LCMS Rt=0.50 min[Method Q], MS (M+1)=532.3. ¹H NMR (METHANOL-d₄) δ 8.16-8.21 (m, 1H),8.06-8.13 (m, 1H), 7.81 (d, J=7.1 Hz, 1H), 7.30 (s, 2H), 6.80 (d, J=2.0Hz, 1H), 6.69 (dd, J=6.8, 2.3 Hz, 1H), 5.02 (br. s., 1H), 3.63 (s, 3H),3.21 (s, 3H), 2.01-2.13 (m, 4H), 1.64 (s, 6H), 1.57 (s, 6H).

Example 26-1 Synthesis of3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol

A mixture of3-hydroxy-5-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate (Intermediate 6-2, 100 mg, 0.193 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(120 mg, 0.579 mmol), and sodium carbonate (102 mg, 0.964 mmol) in 3:1DME/water (1.9 mL) was degassed with a stream of dry nitrogen for 5minutes. Tetrakis(triphenylphosphine)palladium(0) (16.7 mg, 0.014 mmol)was added and the mixture was heated under microwave irradiation at 90°C. for one hour. The mixture was partitioned between water anddichloromethane and the organic phase acidified with HCl in MeOH (4equivalents) and concentrated to dryness. The crude material was loadedonto an SCX column (1 g, preconditioned with MeOH), washed with MeOH,and eluted with 7 N ammonia in MeOH. The eluent was concentrated todryness and purification by flash chromatography (12 g silica, 1-12% 7 Nammonia in MeOH gradient, in DCM) provided3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-phenolas a light yellow solid (55 mg). LCMS Rt=0.44 min [Method Q], MS(M+1)=451.5. ¹H NMR (400 MHz, METHANOL-d4) δ 8.25 (d, J=10.11 Hz, 1H),8.03 (s, 1H), 7.87 (s, 1H), 7.22 (d, J=10.11 Hz, 1H), 6.74-6.85 (m, 2H),5.05 (t, J=12.38 Hz, 1H), 3.95 (s, 3H), 3.95 (s, 3H), 3.01 (s, 3H),1.65-1.75 (m, 2H), 1.50-1.64 (m, 2H), 1.39 (s, 6H), 1.24 (s, 6H).

The following compounds were prepared in a manner similar to that ofExample 26-1.

LCMS Example Compound Method Q ¹H NMR 400 MHz 26-2

M + 1 = 491.4 Rt = 0.48 min (METHANOL-d4) δ 8.25 (d, J = 10.11 Hz, 1H),7.76 (s, 1H), 7.23 (d, J = 10.11 Hz, 1H), 6.69 (dd, J = 1.52, 11.12 Hz,2H), 5.07 (t, J = 12.38 Hz, 1H), 4.19 (t, J = 6.06 Hz, 2H), 3.94 (s,3H), 3.05 (t, J = 6.32 Hz, 2H), 3.02 (s, 3H), 2.08-2.18 (m, 2H),1.91-2.02 (m, 2H), 1.67-1.76 (m, 2H), 1.53-1.64 (m, 2H), 1.40 (s, 6H),1.25 (s, 6H) 26-3

M + 1 = 448.3 Rt = 0.47 min (METHANOL-d4) δ 8.87 (d, J = 1.52 Hz, 1H),8.56 (dd, J = 1.26, 4.80 Hz, 1H), 8.25 (d, J = 9.60 Hz, 1H), 8.12- 8.20(m, 1H), 7.55 (dd, J = 5.05, 8.08 Hz, 1H), 7.24 (d, J = 9.60 Hz, 1H),6.92 (d, J = 1.52 Hz, 1H), 6.88 (d, J = 1.52 Hz, 1H), 5.10 (t, J = 11.87Hz, 1H), 3.99 (s, 3H), 3.03 (s, 3H), 1.67- 1.76 (m, 2H), 1.51-1.65 (m,2H), 1.40 (s, 6H), 1.25 (s, 6H) 26-4

M + 1 = 505.5 Rt = 0.52 min (METHANOL-d4) δ 8.26 (d, J = 9.60 Hz, 1H),8.12 (s, 1H), 7.89 (s, 1H), 7.23 (d, J = 10.11 Hz, 1H), 6.77-6.86 (m,2H), 5.08 (t, J = 12.38 Hz, 1H), 4.75 (quin, J = 7.33 Hz, 1H), 3.96 (s,3H), 3.02 (s, 3H), 2.17-2.31 (m, 2H), 2.01-2.13 (m, 2H), 1.88-2.01 (m,2H), 1.68-1.85 (m, 4H), 1.54-1.67 (m, 2H), 1.42 (s, 6H), 1.26 (s, 6H)26-5

M + 1 = 477.4 Rt = 0.44 min (METHANOL-d4) δ ppm 8.25 (d, J = 10.1 Hz,1H), 7.33-7.43 (m, 1H), 7.16-7.30 (m, 3H), 6.91-7.00 (m, 1H), 6.85 (dd,J = 15.9, 1.8 Hz, 2H), 5.10 (t, J = 12.1 Hz, 1H), 3.97 (s, 3H), 3.88 (s,3H), 3.02 (s, 3H), 1.67-1.77 (m, 2H), 1.54-1.65 (m, 2H), 1.41 (s, 6H),1.25 (s, 6H)

Example 27-1 Synthesis of3-(benzyloxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol

Step 1:3-(Benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)benzoic acid

(2-(Trimethylsilyl)ethoxymethyl chloride (SEM-Cl, 3.10 mL, 17.5 mmol)was added to a mixture of methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate(Example 22-1 Step 1, 5.36 g, 15.9 mmol) and potassium carbonate (5.49g, 39.7 mmol) in DMF (53.0 mL), and the mixture was allowed to stir atroom temperature for two days. An additional portion of SEM-Cl (3.10 mL,17.5 mmol) was added and the mixture stirred an additional 4 hours. Thereaction mixture was partitioned between saturated sodium bicarbonateand 1:1 ethyl acetate/diethyl ether. The organic phase was washed withwater (5×), brine, dried over MgSO₄, and concentrated to a light orangeoil. The crude product was dissolved into 2:1 tetrahydrofuran/methanol(100 mL) and aqueous sodium hydroxide solution (2.0 M, 63.6 mL, 127mmol) was added. The solution was stirred for 1 hour after which timevolatiles were removed via rotary evaporation. The remaining solutionwas acidified to pH 3 by slow addition of concentrated hydrochloricacid, extracted with dichloromethane (1×), then with 1:1 ether/ethylacetate (4×). The combined extracts were washed with brine, dried overMgSO₄ and concentrated to a solid. The crude product was triturated withheptane and dried under vacuum to provide3-(benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)benzoic acid(6.36 g) as a white solid. MS (M+1)=453.4. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.28-7.59 (m, 7H) 5.36 (s, 2H) 5.18-5.28 (m, 2H)3.75-3.90 (m, 2H) 0.92-1.03 (m, 2H) 0.00 (s, 9H).

Step 2:3-(Benzyloxy)-4-bromo-N-(prop-2-ynyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)benzamide

To a mixture of3-(benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)benzoic acid(6.142 g, 13.55 mmol) and Mukaiyama reagent (2-chloro-1-methylpyridiniumiodide, 5.19 g, 20.3 mmol) in dichloromethane (135 mL) was addedtriethylamine (7.55 mL, 54.2 mmol). The solution was stirred for 10minutes after which time propargylamine (1.74 mL, 27.1 mmol) was added.The solution was stirred overnight. The solution was diluted with 1:1ethyl acetate/diethyl ether and washed with water, brine, dried overMgSO₄ and concentrated. The crude product was purified by flashchromatography (40 g silica gel, gradient of ethyl acetate indichloromethane) providing3-(benzyloxy)-4-bromo-N-(prop-2-ynyl)-5-((2-(trimethylsilyl)ethoxy)-methoxy)-benzamideas an orange oil (6.49 g). MS (M+1)=492.2. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.28-7.55 (m, 5H) 7.13 (dd, J=11.37, 1.77 Hz, 2H)6.23 (br. s., 1H) 5.34 (s, 2H) 5.20 (s, 2H) 4.22 (dd, J=5.05, 2.53 Hz,2H) 3.81 (dd, J=9.09, 7.58 Hz, 2H) 2.28 (t, J=2.78 Hz, 1H) 0.91-1.00 (m,2H) −0.03-0.03 (m, 9H).

Step 3:2-(3-(Benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-methyloxazole

Sodium hydride (0.953 g, 39.7 mmol) was added to a solution of3-(benzyloxy)-4-bromo-N-(prop-2-ynyl)-5-((2-(trimethylsilyl)ethoxy)-methoxy)benzamide(6.49 g, 13.2 mmol) in dioxane (100 mL) and the mixture was heated atreflux overnight. The solution was cooled to room temperature andquenched by slow addition of saturated NaHCO₃. The solution was dilutedwith ethyl acetate/diethyl ether and washed with water (5×), saturatedNaHCO₃, brine, dried over sodium sulfate and concentrated to a thickbrown liquid. Flash chromatography (80 g silica gel, 5-40% EtOAc inheptane) provided2-(3-(benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-methyloxazoleas an orange oil (3.33 g). MS (M+1)=492.21. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.30-7.58 (m, 7H), 6.86 (d, J=1.0 Hz, 1H), 5.40 (s,2H), 5.25 (s, 2H), 3.80-3.92 (m, 2H), 2.41 (s, 3H), 0.95-1.04 (m, 2H),0.02 (s, 10H).

Step 4: (2-(Benzyloxy)-6-hydroxy-4-(5-methyloxazol-2-yl)phenyl)boronicacid

To a stirred solution of2-(3-(benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-methyloxazole(1.2 g, 2.447 mmol) in THF (6 mL) cooled to −78° C. was added n-butyllithium (2.5 M in heptane, 1.17 mL, 2.94 mmol) dropwise. The solutionwas stirred for 30 minutes after which time trimethyl borate (0.82 mL,7.34 mmol) was added in a single portion. The cold bath was removed andthe solution was allowed to warm to room temperature over two hours.Aqueous HCl (0.1 M) was added followed by 1:1 ethyl acetate/diethylether. The solution was washed with 0.1 M HCl, water, brine, dried overmagnesium sulfate and concentrated. The resulting solids were washedwith DCM to provide 105 mg of a 3:1 mixture of(2-(benzyloxy)-6-hydroxy-4-(5-methyloxazol-2-yl)phenyl)boronic acid (MS(M+1)=326.2) and 3-(benzyloxy)-5-(5-methyloxazol-2-yl)phenol (MS(M+1)=282.2) as an off-white solid. This mixture was taken on withoutfurther purification.

Step 5:3-(Benzyloxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol

A mixture of6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 45 mg, 0.16 mmol), the crude(2-(benzyloxy)-6-hydroxy-4-(5-methyloxazol-2-yl)phenyl)boronic acid (103mg, 0.239 mmol based on 75% purity), and sodium carbonate (51 mg, 0.48mmol) in 3:1 DME/water was degassed with a stream of dry nitrogen forfive minutes. Tetrakis(triphenylphosphine)palladium(0) (18.39 mg, 0.016mmol) was added and the mixture heated under microwave irradiation at140° C. for 30 minutes. The mixture was diluted with dichloromethane andwashed with water. The organic phase was acidified with HCl in MeOH (3equivalents) and was concentrated to dryness. The crude material wasloaded onto an SCX column (1 g, preconditioned with MeOH), washed withMeOH, and eluted with 7 N ammonia in MeOH. The eluent was concentratedto dryness and purification by flash chromatography (12 g silica, 2-20%7 N ammonia in MeOH gradient, in DCM) provided3-(benzyloxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenolas a light yellow solid. LCMS Rt=0.61 min [Method Q], MS (M+1)=528.5. ¹HNMR (400 MHz, METHANOL-d4) δ ppm 8.18 (d, J=10.10 Hz, 1H), 7.28-7.51 (m,6H), 7.23 (d, J=1.52 Hz, 1H), 7.13 (d, J=10.11 Hz, 1H), 6.95 (d, J=1.52Hz, 1H), 5.25 (s, 2H), 5.14 (t, J=11.87 Hz, 1H), 2.99 (s, 3H), 2.45 (d,J=1.01 Hz, 3H), 1.66-1.75 (m, 2H), 1.53-1.64 (m, 2H), 1.40 (s, 6H), 1.25(s, 6H).

Example 27-2 Synthesis of3-ethoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol

Step 1: 3-(Benzyloxy)-2-bromo-5-(5-methyloxazol-2-yl)phenol

Concentrated hydrochloric acid (3 mL) was added to a solution of2-(3-(benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-methyloxazole(0.60 g, 1.22 mmol) in THF (8 mL) and stirred at room temperature forthree hours. The solution was diluted with water and extracted with 1:1ethyl acetate/diethyl ether (4×). The extracts were washed withsaturated sodium bicarbonate, brine, dried over magnesium sulfate andconcentrated to a solid. The solid was triturated with heptane (2×) anddried under vacuum to provide3-(benzyloxy)-2-bromo-5-(5-methyloxazol-2-yl)phenol as an off whitesolid (412 mg). MS (M+1)=360.2. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm7.52 (d, J=7.07 Hz, 2H), 7.36-7.43 (m, 2H), 7.28-7.35 (m, 2H), 7.23 (d,J=1.52 Hz, 1H), 6.86 (d, J=1.52 Hz, 1H), 5.24 (s, 2H), 4.21 (q, J=6.74Hz, 2H), 2.41 (d, J=1.01 Hz, 3H), 1.50 (t, J=6.82 Hz, 3H).

Step 2: 2-(3-(Benzyloxy)-4-bromo-5-ethoxyphenyl)-5-methyloxazole

Iodoethane (111 uL, 1.37 mmol) was added to a mixture of3-(benzyloxy)-2-bromo-5-(5-methyloxazol-2-yl)phenol (412 mg, 1.14 mmol)and potassium carbonate (632 mg, 4.58 mmol) in DMF (2.8 mL). Afterstirring for two hours, the solution was diluted with 1:1 ethylacetate/diethyl ether, washed with water (5×), brine, dried overmagnesium sulfate and concentrated to provide2-(3-(benzyloxy)-4-bromo-5-ethoxyphenyl)-5-methyloxazole as a whitecrystalline solid (421 mg). MS (M+1)=388.2. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.52 (d, J=7.07 Hz, 2H), 7.36-7.43 (m, 2H),7.28-7.35 (m, 2H), 7.23 (d, J=1.52 Hz, 1H), 6.86 (d, J=1.52 Hz, 1H),5.24 (s, 2H), 4.21 (q, J=6.74 Hz, 2H), 2.41 (d, J=1.01 Hz, 3H), 1.50 (t,J=6.82 Hz, 3H).

Step 3: (2-(Benzyloxy)-6-ethoxy-4-(5-methyloxazol-2-yl)phenyl)boronicacid

The title compound was prepared in a manner analogous to Example 22-1,Step 6. MS (M+1)=354.3. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 7.27-7.46(m, 1H), 7.26 (s, 1H), 7.18 (s, 1H), 6.90 (d, J=1.0 Hz, 1H), 5.14 (s,2H), 4.11 (q, J=7.1 Hz, 2H), 2.40 (d, J=1.0 Hz, 3H), 1.37 (t, J=6.8 Hz,3H).

Step 4:6-(2-(Benzyloxy)-6-ethoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine

The title compound was prepared in a manner analogous to Example 22-1,Step 7. MS (M+1)=556.5

Step 5

3-Ethoxy-2-(6-(methyl(2,2,6-trimethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol.

The title compound was prepared in a manner analogous to Example 22-1,Step 8. LCMS Rt=0.53 min [Method Q], MS (M+1)=466.4. ¹H NMR (400 MHz,METHANOL-d4) δ 8.30 (d, J=9.60 Hz, 1H), 7.26 (d, J=9.60 Hz, 1H), 7.20(d, J=4.04 Hz, 2H), 6.95 (s, 1H), 5.17 (br. s., 1H), 4.23 (q, J=6.91 Hz,2H), 3.03 (s, 3H), 2.45 (s, 3H), 1.72-1.81 (m, 2H), 1.59-1.71 (m, 2H),1.49 (t, J=6.82 Hz, 3H), 1.44 (s, 6H), 1.29 (s, 6H).

Example 27-3 Synthesis of3-(cyclopropylmethoxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol

Step 1:2-(3-(Benzyloxy)-4-bromo-5-(cyclopropylmethoxy)phenyl)-5-methyloxazole

The title compound was synthesized from3-(benzyloxy)-2-bromo-5-(5-methyloxazol-2-yl)phenol (Example 27-2,Step 1) and bromomethyl)cyclopropane in a manner analogous to Example27-2, Step 2. MS (M+1)=416.2. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.23-7.52(m, 7H), 6.83 (d, J=1.01 Hz, 1H), 5.19 (s, 2H), 3.94 (d, J=6.70 Hz, 2H),2.36 (d, J=1.01 Hz, 3H), 1.23-1.35 (m, 1H), 0.53-0.65 (m, 2H), 0.31-0.42(m, 2H).

Step 2:(2-(Benzyloxy)-6-(cyclopropylmethoxy)-4-(5-methyloxazol-2-yl)phenyl)boronicacid

The title compound was prepared in a manner analogous to Example 22-1,Step 6. MS (M+1)=380.3. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.30-7.50(m, 8H), 7.26 (s, 1H), 6.92 (d, J=1.0 Hz, 1H), 5.24 (s, 2H), 4.02 (d,J=7.1 Hz, 2H), 2.45 (d, J=1.0 Hz, 3H), 1.30-1.43 (m, 1H), 0.68-0.78 (m,2H), 0.38-0.45 (m, 2H).

Step 3:6-(2-(Benzyloxy)-6-(cyclopropylmethoxy)-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

The title compound was prepared in a manner analogous to Example 22-1,Step 7. MS (M+1)=582.5.

Step 4:3-(Cyclopropylmethoxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol

The title compound was prepared in a manner analogous to Example 22-1,Step 8. LCMS Rt=0.55 min [Method Q], MS (M−1)=489.9. ¹H NMR (400 MHz,METHANOL-d4) δ 8.43 (d, J=10.11 Hz, 1H), 7.25 (d, J=10.11 Hz, 1H), 7.19(d, J=1.52 Hz, 1H), 7.14 (d, J=1.52 Hz, 1H), 6.94 (d, J=1.01 Hz, 1H),5.13 (t, J=12.13 Hz, 1H), 4.01 (d, J=7.07 Hz, 2H), 3.02 (s, 3H), 2.45(d, J=1.01 Hz, 3H), 1.66-1.75 (m, 2H), 1.52-1.63 (m, 2H), 1.40 (s, 6H),1.30-1.37 (m, 1H), 1.24 (s, 6H), 0.62-0.74 (m, 2H), 0.35-0.46 (m, 2H).

Example 28-1 Synthesis of2-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1H-benzo[d]imidazol-6-ol

Step 1:5-Bromo-6-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

To a mixture of 5-bromo-6-methoxy-2-methyl-1H-benzo[d]imidazole (400 mg,1.659 mmol) in DMF (3 mL) was added 60% wt NaH (80 mg, 1.991 mmol) at 0°C. The mixture was stirred from 0° C. to room temperature for 0.5 hours,then 2-trimethylsilylethyoxymethyl chloride (SEMCl, 0.352 mL, 1.991mmol) was added dropwise. The reaction mixture was stirred at roomtemperature for 2 hours then quenched with water and extracted with DCM.The organic phase was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (10-100%EtOAc/Heptane then 0-10% DCM/MeOH) to afford the title compound (310 mg,50.3% yield) as an oil. MS (M+1)=373.1.

Step 2:6-Methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole,and(6-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)boronicacid

A degassed reaction mixture of5-bromo-6-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole(145 mg, 0.390 mmol), bis(pinacolato) diboron (218 mg, 0.859 mmol),Pd(dppf)Cl₂ (31.9 mg, 0.039 mmol), dppf (21.7 mg, 0.039 mmol) andpotassium acetate (192 mg, 1.95 mmol) in dioxane (1.5 mL) was heated at90° C. overnight. The reaction mixture was filtered through celite andwashed with EtOAc. The filtrate was concentrated to a brown oil. Thecrude product was purified by flash column chromatography (10-100%EtOAc/Heptane) to afford a mixture of6-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazoleand(6-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)boronicacid (126.8 mg, 89.3% total yield), which was used in the next stepwithout further purification. MS (M+1)=419.4 and 337.2, respectively.

Step 3:6-(6-Methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

The mixture of(6-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)boronicacid and the pinacol ester (78 mg, 0.139 mmol), and Intermediate 1-1 (26mg, 0.092 mmol) were reacted according to GENERAL METHOD 1-5 for Suzukicoupling.6-(6-Methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-aminewas obtained after flash column chromatography purification (44 mg, 89%yield). MS (M+1)=539.7.

Step 4:2-Methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1H-benzo[d]imidazol-6-ol

From6-(6-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(44 mg, 0.082 mmol), following General Method 3.2 for methoxydeprotection using BBr₃,2-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1H-benzo[d]imidazol-6-olwas obtained as a white solid after HPLC purification (16 mg, 50%yield). LCMS Rt=0.40 min [Method Q], MS (M+1)=395.4. ¹H NMR(METHANOL-d₄) δ 8.15 (d, J=10.1 Hz, 1H), 7.88 (s, 1H), 7.34 (d, J=9.6Hz, 1H), 6.97 (s, 1H), 5.07 (t, J=11.9 Hz, 1H), 3.02 (s, 3H), 2.55 (s,3H), 1.65-1.77 (m, 2H), 1.51-1.65 (m, 2H), 1.41 (s, 6H), 1.25 (s, 6H).

Example 29-1 Synthesis of5-chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Intermediate 1-1 and5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol werereacted according GENERAL METHOD 1-5 for Suzuki coupling.5-Chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenolwas obtained as a yellow solid after HPLC purification. LCMS Rt=0.54 min[Method Q], MS (M+1)=375.2. ¹H NMR (METHANOL-d₄) δ 8.16 (d, J=9.6 Hz,1H), 7.74 (d, J=8.6 Hz, 1H), 7.45 (d, J=10.1 Hz, 1H), 6.91-7.05 (m, 2H),5.28-5.44 (m, 1H), 3.06 (s, 3H), 1.88-2.05 (m, 4H), 1.65 (s, 6H), 1.52(s, 6H).

Example 30-1 Synthesis of5-(1H-pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Step 1

6-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(148 mg, 0.353 mmol, 48% yield) was prepared following GENERAL METHOD1-4 for Suzuki coupling from1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-1H-pyrazole(Intermediate 2-1, Step 3, 447 mg, 1.49 mmol) and Intermediate 1-2 (200mg, 0.744 mmol). LCMS Rt=0.95 min (LCMS condition B); MS (M+1)=407.3. ¹HNMR (400 MHz, CHLOROFORM-d) δ 7.97-8.06 (m, 2H), 7.73-7.82 (m, 2H), 7.52(d, J=2.01 Hz, 1H), 7.24-7.31 (m, 1H), 6.64 (d, J=9.29 Hz, 1H),6.47-6.54 (m, 1H), 4.49 (d, J=8.03 Hz, 1H), 4.27-4.42 (m, 1H), 3.95 (s,3H), 2.12 (dd, J=3.76, 12.55 Hz, 2H), 1.33 (s, 6H), 1.17 (s, 6H), 1.03(t, J=12.05 Hz, 2H).

Step 2:5-(1H-Pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Following GENERAL METHOD 3-1 for methoxy deprotection using thiophenol,the title compound was afforded as pale yellow powder (8 mg). LCMSRt=0.48 min [Method Q]; MS (M+1)=393.3. ¹H NMR (400 MHz, METHANOL-d4) δ8.29 (d, J=2.51 Hz, 1H), 8.05 (d, J=9.79 Hz, 1H), 7.89 (d, J=8.53 Hz,1H), 7.76 (d, J=1.51 Hz, 1H), 7.32-7.40 (m, 2H), 7.06 (d, J=9.79 Hz,1H), 6.56 (t, J=2.13 Hz, 1H), 4.41-4.56 (m, 1H), 2.08 (dd, J=3.51, 12.80Hz, 2H), 1.40 (s, 6H), 1.16-1.27 (m, 8H).

Example 30-2 Synthesis of3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile

To a microwave vial was added3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile(Example 5-1, Step 1, 100 mg, 0.264 mmol) and pyridine hydrochloride(610 mg, 5.27 mmol), and the mixture was heated at 150° C. for 90minutes in the microwave. The reaction mixture is dissolved inMeOH/DMSO, and purified by preparative HPLC (Waters Sunfire 30 mm ID×50mm, 0.1% TFA, 15-40% ACN/H₂O) to provide the title compound as a minorproduct (3 mg, 0.008 mmol). LCMS Rt=0.47 min (Method Q); MS (M+1)=352.2.¹H NMR (400 MHz, CHLOROFORM-d) δ 7.81 (d, J=9.54 Hz, 1H), 7.65 (d,J=8.03 Hz, 1H), 7.34 (d, J=1.51 Hz, 1H), 7.18 (dd, J=1.76, 8.28 Hz, 1H),6.87 (d, J=9.54 Hz, 1H), 4.83 (br. s., 1H), 4.40 (d, J=7.53 Hz, 1H),2.11 (dd, J=3.64, 12.67 Hz, 2H), 1.59 (td, J=7.72, 15.18 Hz, 1H),1.33-1.43 (m, 7H), 1.25 (br. s., 6H).

Example 31-1 Synthesis of2-(6-((2,2-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

Potassium tert-butoxide (1.0 M in THF, 2.2 mL, 2.2 mmol) was added to2,2-dimethylpiperidin-4-ol (0.22 g, 1.66 mmol) in THF (2.2 mL) and DMF(0.6 mL) and the mixture was stirred for 10 minutes at 50° C.Intermediate 2-2 (0.15 g, 0.55 mmol) was added to the reaction at 0° C.and the mixture was stirred for 4 h at RT. A solution of sodiumbicarbonate was added and the aqueous phase was extracted with 3:1chloroform propan-2-ol (2×). The combined organic phases were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude material was purified via preparative HPLC (10 to 60% acetonitrilein water, 0.1% trifluoroacetic acid as modifier). The appropriatefractions containing product were free based by catch and release usingSiliaBond Tosic Acid® (5 g, MeOH as eluent and a 2 N ammonia solution inMeOH to release the material). Evaporation under reduced pressureafforded2-(6-((2,2-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenolas a beige solid (0.11 g, 53%). LCMS Rt=0.52 min [Method Q]; [M+H]:366.2; ¹H NMR (400 MHz, DMSO) δ 13.30 (bs, 1H), 8.60 (d, J=2.5 Hz, 1H),8.44 (d, J=9.5 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H),7.50 (d, J=2.0 Hz, 1H), 7.48 (dd, J=8.5, 2.0 Hz, 1H), 7.40 (d, J=9.5 Hz,1H), 6.61-6.54 (m, 1H), 5.45 (td, J=10.5, 5.0 Hz, 1H), 2.94-2.76 (m,2H), 2.16-2.05 (m, 1H), 2.03-1.96 (m, 1H), 1.49-1.30 (m, 2H), 1.13 (s,3H), 1.10 (s, 3H).

Example 32-1 Synthesis of2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-4-yl)phenol

Step 1: 4-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

Following GENERAL METHOD 2-1 for boronate ester formation using3-bromo-4-methoxyphenol (1.0 g, 4.90 mmol) affords4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.23mg) MS [M+H⁺]=251.1.

Step 2:4-Methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

To a microwave vial was added4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (400 mg,1.60 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 452 mg, 1.60 mmol), potassium phosphate (1.4 g, 6.40mmol), Pd₂(dba)₃ (146 mg, 0.16 mmol), and SPhos (65.7 mg, 0.16 mmol),followed by addition of 1,4-dioxane (4 mL)/H₂O (0.8 mL). The vial waspurged with N₂ for 5 minutes and the reaction mixture was heated at 100°C. in the microwave for 2 h. The reaction mixture was concentrated invacuo. The crude material was adjusted to pH 3 using 12 M HCl aqueoussolution and loaded onto an SCX column. The crude material was washedwith methanol then eluted with 2 N ammonia in methanol. Theproduct-containing fractions were concentrated to afford4-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(491 mg) MS [M+H⁺]=371.2.

Step 3:4-Methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate

To a solution of4-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(490 mg, 1.32 mmol) in DCM (8 mL) was added triethylamine (0.461 mL,3.31 mmol) at RT. The reaction mixture was cooled to 0° C., followed byaddition of N-phenyltrifluoromethanesulfonimide (472 mg, 1.32 mmol). Thereaction mixture was warmed to RT and stirred for two hours thenquenched with aqueous sodium bicarbonate solution and extracted withDCM. The organic layer was dried over sodium sulfate, filtered andconcentrated to give the crude product which was adjusted to pH 3 using1 M HCl aqueous solution and loaded onto an SCX column. The crudeproduct was washed with methanol then eluted with 2 N ammonia inmethanol. The product fractions were collected and dried to afford4-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate (665 mg) MS [M+H⁺]=503.2.

Step 4:6-(2-Methoxy-5-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a microwave vial was added4-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate (100 mg, 0.20 mmol), 1H-pyrazol-4-ylboronicacid (33.4 mg, 0.30 mmol), potassium phosphate (127 mg, 0.60 mmol),Pd₂(dba)₃ (18.22 mg, 0.02 mmol), and SPhos (16.4 mg, 0.04 mmol),followed by addition of 1,4-dioxane (1.6 mL)/H₂O (0.4 mL). The vial waspurged with N₂ for 5 minutes and the reaction mixture was heated at 100°C. in the microwave for 1 hour. The reaction mixture was concentrated invacuo. The crude material was adjusted to pH 3 using 1 M HCl aqueoussolution and loaded on an SCX column. The crude material was washed withmethanol then eluted with 2 N ammonia in methanol. Theproduct-containing fractions were concentrated to afford6-(2-methoxy-5-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(68 mg) MS [M+H⁺]=421.3.

Step 5:2-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-4-yl)phenol

Following standard GENERAL METHOD 3-2 for methoxy deprotection, thetitle compound was afforded. MS [M+H⁺]=407.3, LCMS Rt=0.51 min [MethodQ]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.42 (d, J=9.79 Hz, 1H), 7.99-8.12(m, 3H), 7.48 (d, J=7.78 Hz, 1H), 7.35 (d, J=9.79 Hz, 1H), 6.90 (d,J=8.28 Hz, 1H), 4.84-5.10 (m, 1H), 2.97 (s, 3H), 1.49-1.58 (m, 2H),1.37-1.49 (m, 2H), 1.23-1.28 (m, 7H), 1.09 (s, 6H).

The following compounds were prepared using similar procedures asdescribed in Example 32-1, followed by methoxy deprotection as outlinedin GENERAL METHODS 3-1 and 3-2 when appropriate.

LCMS Example Compound Method Q ¹HNMR 400 MHz 32-2

M + 1 = 461.4 Rt = 0.52 min (DMSO-d₆) δ ppm 13.48 (br. s., 1H), 8.30 (d,J = 10.04 Hz, 1H), 7.83 (d, J = 2.01 Hz, 1H), 7.74 (s, 1H), 7.27-7.41(m, 2H), 6.96 (d, J = 8.53 Hz, 1H), 4.74-5.12 (m, 1H), 4.10 (t, J = 6.02Hz, 2H), 2.84-3.09 (m, 5H), 1.92-2.09 (m, 2H), 1.75- 1.90 (m, 2H),0.89-1.67 (m, 17H) 32-3

M + 1 = 462.4 Rt = 0.38 min (DMSO-d₆) δ ppm 13.44- 13.57 (m, 1H),8.28-8.38 (m, 1H), 7.76-7.86 (m, 2H), 7.31- 7.41 (m, 1H), 7.20-7.29 (m,1H), 6.92-7.02 (m, 1H), 4.84- 5.08 (m, 1H), 3.90-4.29 (m, 5H), 3.09-3.19(m, 2H). 2.97 (s, 3H), 1.39-1.58 (m, 4H), 1.24-1.30 (m, 7H), 1.09 (s,6H) 32-4

M + 1 = 456.4 Rt = 0.58 min (DMSO-d₆) δ ppm 13.77 (s, 1H), 11.48 (s,1H), 8.41 (d, J = 10.04 Hz, 1H), 8.35 (d, J = 2.01 Hz, 1H), 7.78 (dd, J= 8.53, 2.01 Hz, 1H), 7.33- 7.57 (m, 3H), 6.94-7.14 (m, 3H), 6.85-6.92(m, 1H), 4.74- 5.29 (m, 1H), 2.99 (s, 3H), 1.38-1.66 (m, 4H), 1.27 (s,6H), 1.10 (s, 6H) 32-5

M + 1 = 407.4 Rt = 0.59 min (METHANOL-d₄) δ ppm 8.15 (d, J = 10.04 Hz,1H), 7.79 (d, J = 2.01 Hz, 1H), 7.42 (dd. J = 8.53, 2.01 Hz, 1H), 7.32(d, J = 9.79 Hz, 1H), 6.92 (d, J = 8.53 Hz, 1H), 6.15 (t, J = 1.88 Hz,1H), 5.02-5.19 (m, 1H), 3.02 (s, 3H), 2.70-2.83 (m, 2H), 2.49-2.61 (m,2H), 1.98- 2.15 (m, 2H), 1.67-1.79 (m, 2H), 1.52-1.66 (m, 2H), 1.42 (s,6H), 1.26 (s, 6H) 32-6

M + 1 = 407.4 Rt = 0.48 min (METHANOL-d4) δ ppm 8.22 (d, J = 9.79 Hz,2H), 7.68 (d, J = 7.28 Hz, 2H), 7.36 (d, J = 9.79 Hz, 1H), 7.03 (d, J =8.53 Hz, 1H), 6.69 (d, J = 1.25 Hz, 1H), 5.18 (t, J = 11.29 Hz, 1H),3.03 (s, 3H), 1.59-1.85 (m, 4H), 1.46 (s, 6H), 1.31 (s, 6H) 32-7

M + 1 = 434.4 Rt = 0.47 min (METHANOL-d₄) δ ppm 8.13 (d, J = 10.1 Hz,1H), 7.95 (d, J = 2.5 Hz, 1H), 7.51 (dd, J = 8.6, 2.0 Hz, 1H), 7.35-7.41(m, 1H), 7.20 (d, J = 10.1 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.58- 6.76(m, 2H), 5.01 (m, 1H), 2.93 (s, 3H), 1.64 (dd, J = 12.6, 3.5 Hz, 2H),1.50 (t, J = 12.4 Hz, 2H), 1.32 (s, 6H), 1.16 (s, 6H) 32-8

M + 1 = 435.4 Rt = 0.48 min ¹H NMR (DMSO-d₆) δ ppm 13.01 (br. s., 1H),8.58 (d, J = 9.1 Hz, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.63-7.72 (m, 2H),7.33 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 2.0 Hz,1H), 6.62 (dd, J = 7.3, 2.3 Hz, 1H), 5.61 (m, 1H), 3.38 (s, 3H), 2.03(dd, J = 11.9, 3.8 Hz, 2H), 1.18-1.26 (m, 2H), 1.17 (s, 6H), 1.04 (s,6H) 32-9

M + 1 = 421.4 Rt = 0.47 min (METHANOL-d₄) δ ppm 8.36 (d, J = 9.1 Hz,1H), 8.06 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 6.1 Hz, 1H),7.18 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.68-6.77 (m, 2H),5.67 (m, 1H), 2.15 (dd, J = 12.6, 4.0 Hz, 2H), 1.35 (t, J = 11.9 Hz,2H), 1.28 (s, 6H), 1.16 (s, 6H)

The following compound was prepared using a similar procedure asdescribed in Example 14-1, utilizing methoxy deprotection as outlined inGENERAL METHOD 3-2:

LCMS NVP Compound Method Q ¹HNMR 400 MHz 33-1

M + 1 = 457.4 Rt = 0.58 min (DMSO-d₆) δ ppm 13.84 (s, 1H), 13.28 (br.s., 1H), 8.31 (d, J = 10.04 Hz, 1H), 8.19 (s, 1H), 8.04 (d, J = 8.28 Hz,1H), 7.79 (d, J = 8.03 Hz, 1H), 7.46 (dd, J = 7.15, 0.63 Hz, 1H), 7.40(d, J = 9.79 Hz, 1H), 7.18-7.30 (m, 3H), 4.84-5.11 (m, 1H), 2.98 (s,3H), 1.39-1.62 (m, 4H), 1.27 (s, 7H) 1.07-1.12 (m, 6H)

Example 34-1 Synthesis of4-chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Step 1: 4-(4-Bromo-2-chloro-5-methoxyphenyl)-1H-pyrazole

Following standard GENERAL METHOD 1-4 for Suzuki coupling using(1H-pyrazol-4-yl)boronic acid (161 mg, 1.44 mmol) and1-bromo-5-chloro-4-iodo-2-methoxybenzene (500 mg, 1.44 mmol) afforded4-(4-bromo-2-chloro-5-methoxyphenyl)-1H-pyrazole (300 mg) MS[M+H⁺]=286.8.

Step 2:4-(2-Chloro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole

Following GENERAL METHOD 2-1 for boronate ester formation using4-(4-bromo-2-chloro-5-methoxyphenyl)-1H-pyrazole (300 mg, 1.04 mmol)afforded4-(2-chloro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(178 mg) MS [M+H⁺]=335.2.

Step 3:6-(5-Chloro-2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Following standard GENERAL METHOD 1-4 for Suzuki coupling using4-(2-chloro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(118 mg, 0.35 mmol) and6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1,100 mg, 0.35 mmol) afforded6-(5-chloro-2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(138 mg) MS [M+H⁺]=455.0.

Step 4:4-Chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Following standard GENERAL METHOD 3-2 for methoxy deprotection, thetitle compound was prepared. MS [M+H⁺]=441.3, LCMS Rt=0.54 min [MethodQ]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.72 (br. s., 1H), 13.13 (br. s.,1H), 8.29 (d, J=10.04 Hz, 1H), 8.04-8.26 (m, 2H), 8.01 (s, 1H), 7.35 (d,J=9.79 Hz, 1H), 7.20 (s, 1H), 4.81-5.23 (m, 1H), 2.95 (s, 3H), 1.36-1.63(m, 4H), 0.96-1.32 (m, 12H).

Example 34-2 Synthesis of4-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Step 1: tert-Butyl4-(2-fluoro-4-hydroxy-5-methoxyphenyl)-1H-pyrazole-1-carboxylate

To a reaction flask was added 4-bromo-5-fluoro-2-methoxyphenol (500 mg,2.26 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(998 mg, 3.39 mmol), potassium phosphate (1.4 g, 6.79 mmol), andXPhosPalladacycle (178 mg, 0.23 mmol), followed by addition of DMF (11mL). The vial was purged with N₂ for 5 minutes and the reaction mixturewas heated at 50° C. in the microwave for 16 h. The reaction mixture wasconcentrated in vacuo and the crude product was purified by silica gelto afford tert-butyl4-(2-fluoro-4-hydroxy-5-methoxyphenyl)-1H-pyrazole-1-carboxylate (700mg) MS [M+H⁺]=307.5.

Step 2: tert-Butyl4-(2-fluoro-5-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1H-pyrazole-1-carboxylate

To a solution of tert-butyl4-(2-fluoro-4-hydroxy-5-methoxyphenyl)-1H-pyrazole-1-carboxylate (700mg, 2.27 mmol) in DCM (11.4 mL) was added triethylamine (01.27 mL, 9.08mmol) at RT. The reaction mixture was cooled to 0° C., followed byaddition of N-phenyltrifluoromethanesulfonimide (973 mg, 2.72 mmol). Thereaction mixture was warmed to RT and stirred for two hours. Thereaction was quenched with aqueous sodium bicarbonate solution andextracted with DCM. The organic layer was dried over sodium sulfate,filtered and concentrated to give the crude product, which was purifiedon silica gel to afford tert-butyl4-(2-fluoro-5-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1H-pyrazole-1-carboxylate(724 mg) MS [M+H⁺—BOC]=341.0.

Step 3: tert-Butyl4-(2-fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole-1-carboxylate

Following GENERAL METHOD 2-1 for boronate ester formation usingtert-butyl4-(2-fluoro-5-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1H-pyrazole-1-carboxylate(635 mg, 1.44 mmol) afforded the title compound (170 mg). MS[M+H⁺]=419.3.

Step 4: tert-Butyl4-(2-fluoro-5-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1H-pyrazole-1-carboxylate

To a microwave vial was added tert-butyl4-(2-fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole-1-carboxylate(98 mg, 0.23 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 66.3 mg, 0.23 mmol), potassium phosphate (199 mg,0.94 mmol), Pd₂(dba)₃ (21.5 mg, 0.02 mmol), and SPhos (9.62 mg, 0.02mmol), followed by addition of 1,4-dioxane (0.4 mL)/H₂O (0.9 mL). Thevial was purged with N₂ for 5 minutes and then heated at 100° C. in themicrowave for one hour. The reaction mixture was concentrated in vacuo.The crude material was adjusted to pH 3 using 1 M HCl aqueous solutionand loaded on an SCX column. The crude material was washed with methanolthen eluted with 2 N ammonia in methanol. The product-containingfractions were concentrated to afford tert-butyl4-(2-fluoro-5-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1H-pyrazole-1-carboxylate(126 mg) MS [M+H⁺]=539.2.

Step 5:4-Fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Following standard GENERAL METHOD 3-2 for methoxy deprotection, thetitle compound was afforded. MS [M+H⁺]=425.3, LCMS Rt=0.48 min [MethodQ]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.58 (s, 1H), 13.15 (br. s., 1H),7.90-8.39 (m, 3H), 7.83 (d, J=12.55 Hz, 1H), 7.24-7.41 (m, 2H),4.80-5.17 (m, 1H), 2.95 (s, 3H), 1.38-1.56 (m, 4H), 1.25 (s, 6H), 1.09(s, 6H).

Example 34-3 Synthesis of5-fluoro-4-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Step 1:6-(4-Fluoro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a microwave vial was added2-(4-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(535 mg, 2.12 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 500 mg, 1.77 mmol), potassium phosphate (1.5 g, 7.07mmol), Pd₂(dba)₃ (162 mg, 0.18 mmol), and SPhos (72.6 mg, 0.18 mmol),followed by addition of 1,4-dioxane (3.7 mL)/H₂O (0.7 mL). The vial waspurged with N₂ for 5 minutes and the reaction mixture was heated at 100°C. in the microwave for one hour. The reaction mixture was concentratedin vacuo. The crude material was adjusted to pH 3 using 1 M HCl aqueoussolution, loaded on an SCX column and washed with methanol, then elutedwith 2 N ammonia in methanol. The product-containing fractions wereconcentrated to afford6-(4-fluoro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(620 mg) MS [M+H⁺]=373.3.

Step 2:(2-Fluoro-4-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)boronicacid

Following GENERAL METHOD 7-1 for Ir Borylation using6-(4-fluoro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(100 mg, 0.23 mmol) afforded(2-fluoro-4-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)boronicacid (101 mg) MS [M+H⁺]=417.3.

Step 3:6-(4-Fluoro-5-(1H-imidazol-4-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Following standard GENERAL METHOD 1-4 for Suzuki coupling using(2-fluoro-4-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)boronicacid (50 mg, 0.12 mmol) and 4-bromo-1H-imidazole (35.3 mg, 0.24 mmol)afforded6-(4-fluoro-5-(1H-imidazol-4-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(52.7 mg) MS [M+H⁺]=439.3.

Step 4:5-Fluoro-4-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Following standard GENERAL METHOD 3-2 for methoxy deprotection, thetitle compound was prepared. MS [M+H⁺]=425.3, LCMS Rt=0.42 min [MethodQ]; ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.18-8.27 (m, 2H), 8.12 (d,J=10.04 Hz, 1H), 7.49 (d, J=2.26 Hz, 1H), 7.32 (d, J=10.04 Hz, 1H), 6.73(d, J=12.55 Hz, 1H), 5.23-5.43 (m, 1H), 2.95 (s, 3H), 1.84-1.95 (m, 4H),1.56 (s, 6H), 1.42 (s, 6H).

The following final compounds were prepared using similar procedures asdescribed in Example 34-3:

LCMS NVP Compound Method Q ¹HNMR 400 MHz 34-4

M + 1 = 425.3 Rt = 0.49 min (METHANOL-d₄) δ ppm 8.13- 8.30 (m, 1H),7.94-8.12 (m, 3H) 7.28-7.39 (m, 1H), 6.77 (d, J = 12.30 Hz, 1H),5.04-5.18 (m, 1H), 3.02 (s, 3H), 1.53-1.74 (m, 5H), 1.40 (s, 7H), 1.25(s, 7H) 34-5

M + 1 = 425.3 Rt = 0.52 (METHANOL-d₄) δ ppm 8.27 (d, J = 7.53 Hz, 1H),8.16 (d, J = 10.04 Hz, 1H), 7.71 (s, 1H), 7.36 (d, J = 10.04 Hz, 1H),6.79 (d, J = 12.80 Hz, 1H), 6.69 (dd, J = 3.51, 2.26 Hz, 1H), 5.05-5.20(m, 1H), 3.03 (s, 3H), 1.66-1.80 (m, 2H), 1.52-1.66 (m, 2H), 1.41 (s,6H), 1.25 (s, 6H)

Example 35-1 Synthesis of6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one

Step 1:6-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one

Following GENERAL METHOD 2-1 for boronate ester formation using5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-one (1.0 mg, 4.15 mmol)afforded6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one(1.16 g) MS [M+H⁺]=289.2.

Step 2:6-Methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one:Intermediate 7-1

Following standard GENERAL METHOD 1-4 for Suzuki coupling using6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one(300 mg, 1.06 mmol) and6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 611 mg, 2.12 mmol) afforded6-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one(433 mg) MS [M+H⁺]=409.7.

Step 3:6-Hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one

Following standard GENERAL METHOD 3-2 for methoxy deprotection, thetitle compound was prepared. MS [M+H⁺]=395.2, LCMS Rt=0.47 min [MethodQ]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.50 (s, 1H), 8.29 (d, J=10.04 Hz,1H), 8.10 (s, 1H), 7.37 (d, J=10.04 Hz, 1H), 7.08 (s, 1H), 4.86-5.27 (m,1H), 3.02-3.11 (m, 2H), 2.97 (s, 3H), 2.62-2.72 (m, 2H), 1.37-1.59 (m,4H), 1.25 (s, 6H), 1.09 (s, 6H).

Example 35-2 Synthesis of6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1,4-dihydroindeno[1,2-c]pyrazol-7-ol

Step 1:6-(7-Methoxy-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a 100 mL round bottom flask containing toluene (1.0 mL) was added6-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one(Intermediate 7-1, 330 mg, 0.81 mmol), ethyl formate (0.13 mL, 1.62mmol), and sodium hydride (97 mg, 2.42 mmol). The reaction mixture wasstirred at RT for 16 h then concentrated in vacuo. Ethanol (5.0 mL),acetic acid (0.51 mL, 8.89 mmol) and hydrazine hydrate (0.53 mL, 10.50mmol) were added. The mixture was refluxed at 80° C. for 3 h andconcentrated in vacuo. The crude material was adjusted to pH 3 using 1 MHCl aqueous solution and loaded onto an SCX column. The crude materialwas washed with methanol then eluted with 2 N ammonia in methanol. Theproduct-containing fractions were concentrated to afford6-(7-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(75 mg) MS [M+H⁺]=433.5.

Step 2:6-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1,4-dihydroindeno[1,2-c]pyrazol-7-ol

Following standard GENERAL METHOD 3-2 for methoxy deprotection, thetitle compound was afforded. MS [M+H⁺]=419.2, LCMS Rt=0.47 min [MethodQ]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.86 (s, 1H), 12.82 (br. s., 1H),8.24 (d, J=10.04 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 7.37 (d, J=10.04Hz, 1H), 7.13 (s, 1H), 4.78-5.12 (m, 1H), 3.60 (s, 2H), 2.96 (s, 3H),1.36-1.64 (m, 4H), 1.18-1.35 (m, 7H), 1.09 (br. s., 6H).

Example 35-3 Synthesis of6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-oneoxime hydrochloride salt

To a microwave vial was added6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one(Example 35-1,150 mg, 0.38 mmol), hydroxylamine hydrochloride (264 mg,3.80 mmol), pyridine (0.25 mL, 3.04 mmol) and MeOH (1.0 mL). Theresulting suspension was stirred at RT for 1.5 hours. The reactionmixture was acidified with excess acetic acid and loaded onto an SCXcolumn. The crude material was washed with methanol then eluted with 2 Nammonia in methanol. The product-containing fractions were concentratedto afford the title compound. MS [M+H⁺]=410.2, LCMS Rt=0.48 min [MethodQ]; ¹H NMR (400 MHz, DMSO-d₆) ppm 10.94-11.13 (m, 1H), 8.91-9.21 (m,1H), 8.29 (d, J=10.04 Hz, 1H), 8.09-8.21 (m, 1H), 7.83 (s, 1H),7.52-7.73 (m, 1H), 7.08 (s, 1H), 4.83-5.31 (m, 1H), 2.91-3.04 (m, 5H),2.74-2.85 (m, 2H), 1.91-2.09 (m, 2H), 1.79 (d, J=10.79 Hz, 2H), 1.53 (s,6H), 1.47 (s, 6H).

Example 35-4 Synthesis of5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-indene-1,6-diol

To a microwave vial was added6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one(Example 35-1, 50 mg, 0.13 mmol), sodium borohydride (9.59 mg, 0.25mmol) and MeOH (1.5 mL). The resulting suspension was stirred at RT fortwo hours. The reaction mixture was acidified with excess acetic acidand loaded onto an SCX column. The crude material was washed withmethanol then eluted with 2 N ammonia in methanol. Theproduct-containing fractions were concentrated to afford the titlecompound. MS [M+H⁺]=397.3, LCMS Rt=0.46 min [LCMS Method Q]; ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.11 (d, J=9.54 Hz, 1H), 7.64 (s, 1H), 7.31 (d,J=9.54 Hz, 1H), 6.99 (s, 1H), 5.16 (t, J=6.53 Hz, 1H), 5.01-5.13 (m,1H), 2.95-3.08 (m, 4H), 2.73-2.86 (m, 1H), 2.41-2.54 (m, 1H), 1.91 (s,1H), 1.53-1.78 (m, 4H), 1.41 (s, 6H), 1.26 (s, 6H).

Example 35-5 Synthesis of2-amino-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-8H-indeno[1,2-d]thiazol-5-olhydrochloride salt

Step 1:5-Methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-8H-indeno[1,2-d]thiazol-2-amine

To a microwave vial containing ethanol (1.2 mL) was added6-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one(Intermediate 7-1, 100 mg, 0.25 mmol), thiourea (55.9 mL, 0.73 mmol),and iodine (124 mg, 0.49 mmol). The reaction mixture was stirred at 100°C. for 3 hours. The mixture was diluted with MeOH and loaded onto an SCXcolumn. The crude material was washed with methanol then eluted with 2 Nammonia in methanol. The product-containing fractions were concentratedto afford5-methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-8H-indeno[1,2-d]thiazol-2-amine(114 mg) MS [M+H⁺]=465.0.

Step 2:2-Amino-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-8H-indeno[1,2-d]thiazol-5-ol

Following standard GENERAL METHOD 3-2 for methoxy deprotection, thetitle compound was prepared. MS [M+H⁺]=451.2, LCMS Rt=0.46 min [MethodQ]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.25-9.36 (m, 1H), 8.36-8.44 (m,1H), 8.33 (d, J=9.85 Hz, 1H), 7.89 (s, 1H), 7.75-7.85 (m, 1H), 7.21 (s,1H), 4.76-5.12 (m, 1H), 3.76 (s, 2H), 3.04 (s, 3H), 2.08 (t, J=12.88 Hz,2H), 1.72-1.88 (m, 2H), 1.44-1.60 (m, 12H).

Example 35-6 Synthesis of9-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5,6-dihydroimidazo[5,1-a]isoquinolin-8-olhydrochloride salt

Step 1: tert-Butyl 4-hydroxy-3-methoxyphenethylcarbamate

To a 250 mL round bottom flask containing DCM (86 mL) was added4-(2-aminoethyl)-2-methoxyphenol hydrochloride (3.5 g, 17.19 mmol), TEA(7.2 mL, 51.6 mmol) and Boc-anhydride (3.94 mg, 18.04 mmol). Theresulting mixture was stirred at RT for 18 hours then diluted with DCM,washed with H₂O, 1 N aqueous HCl, and brine, then the organic layer wasdried with sodium sulfate and concentrated in vacuo to afford tert-butyl4-hydroxy-3-methoxyphenethylcarbamate (4.59 g). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.71 (s, 1H), 6.85 (t, J=5.52 Hz, 1H), 6.72 (d, J=1.76Hz, 1H), 6.63-6.68 (m, 1H), 6.55 (dd, J=8.03, 1.76 Hz, 1H), 3.74 (s,3H), 3.01-3.13 (m, 2H), 2.53-2.62 (m, 2H), 1.37 (s, 9H).

Step 2: tert-Butyl 4-isopropoxy-3-methoxyphenethylcarbamate

To a 250 mL round bottom flask containing acetonitrile (18.7 mL) wasadded tert-butyl 4-hydroxy-3-methoxyphenethylcarbamate (1.0 g, 3.74mmol), 2-bromopropane (0.51 g, 4.11 mmol), and potassium carbonate (1.5g, 11.22 mmol). The resulting suspension was stirred at 65° C. for 18hours. A second addition of 2-bromopropane (0.51 g, 4.11 mmol) wasperformed and heating was continued for another 18 hours. The reactionmixture was concentrated reaction in vacuo. The resulting oil wasdissolved in EtOAc and washed with H₂O, aqeuous saturated sodiumbicarbonate and brine, then dried with sodium sulfate and concentratedin vacuo. The crude product was purified by silica gel chromatography(0-100% EtOAc in Heptane) to afford tert-butyl4-isopropoxy-3-methoxyphenethylcarbamate (0.81 g). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 6.84 (d, J=8.03 Hz, 1H), 6.67-6.75 (m, 2H),4.37-4.70 (m, 2H), 3.86 (s, 3H), 3.27-3.46 (m, 2H), 2.68-2.81 (m, 2H),1.45 (s, 9H), 1.37 (d, J=6.02 Hz, 6H).

Step 3: 2-(4-Isopropoxy-3-methoxyphenyl)ethanamine hydrochloride

In a 50 mL round bottom flask was combined tert-butyl4-isopropoxy-3-methoxyphenethylcarbamate (810 mg, 2.62 mmol) and HCl (4Min 1,4-dioxane) (6.5 mL, 26.2 mmol). The suspension was stirred at RTfor two hours then concentrated in vacuo to afford2-(4-isopropoxy-3-methoxyphenyl)ethanamine hydrochloride (643 mg) MS[M+H⁺]=210.3.

Step 4: 2-Formamido-N-(4-isopropoxy-3-methoxyphenethyl)acetamide

2-(4-Isopropoxy-3-methoxyphenyl)ethanamine hydrochloride (487 mg, 2.33mmol) was taken up in MeOH and loaded onto an SCX column. The crudematerial was washed with methanol then eluted with 2 N ammonia inmethanol. The product-containing fractions were concentrated to affordthe free base 2-(4-isopropoxy-3-methoxyphenyl)ethanamine. This materialwas dissolved in THF (23.3 mL) and 2-formamidoacetic acid (360 mg, 3.49mmol), DCC (528 mg, 2.56 mmol), HOBt (392 mg, 2.56 mmol), and NMM (1.02mL, 9.31 mmol) were added. The resulting suspension was stirred at RTfor 3 hours, diluted with ether and filtered through celite. Thefiltrate was purified by silica gel chromoatorgraphy (25%-50% AcOH inDCM) to afford 2-formamido-N-(4-isopropoxy-3-methoxyphenethyl)acetamide(650 mg) MS [M+H⁺]=295.3.

Step 5: 9-Isopropoxy-8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinoline

To a 50 mL round bottom flask was added2-formamido-N-(4-isopropoxy-3-methoxyphenethyl)acetamide (600 mg, 2.04mmol) followed by acetonitrile (10.2 mL) and POCl₃ (0.57 mL, 6.12 mmol).The reaction mixture was heated to 80° C. for one hour then concentratedin vacuo. To the resulting oil was added H₂O and aqueous saturatedsodium carbonate, then the solution was extracted with EtOAc (2×). Theorganic extracts were combined, dried with sodium sulfate andconcentrated in vacuo. The crude product was purified by silica gelchromatography (0-10% MeOH in DCM) to afford9-isopropoxy-8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinoline (182 mg) MS[M+H⁺]=259.2.

Step 6: 8-Methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-ol

To a 50 mL round bottom flask was added9-isopropoxy-8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinoline (180 mg,0.70 mmol), chloroform (13 mL), and methanesulfonic acid (1.3 mL, 20.02mmol). The resulting mixture was heated at 63° C. for 2 h then cooled toRT and concentrated in vacuo. To the resulting oil was added H₂O andaqueous saturated sodium carbonate. The solution was extracted withEtOAc (2×), and the organic extracts were combined, dried with sodiumsulfate and concentrated in vacuo to afford8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-ol. (151 mg) MS[M+H⁺]=217.4.

Step 7: 8-Methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-yltrifluoromethanesulfonate

To a solution of 8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-ol(196 mg, 2.27 mmol) in DCM (5.5 mL) was added triethylamine (0.38 mL,2.72 mmol) at RT. The reaction mixture was cooled to 0° C., followed byaddition of N-phenyltrifluoromethanesulfonimide (356 mg, 0.98 mmol). Thereaction mixture was warmed to RT and stirred for 2 h. The reaction wasquenched with aqueous sodium bicarbonate solution and extracted withDCM. The organic layer was dried over sodium sulfate, filtered andconcentrated to give the crude product, which was purified on silica gelto provide 8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-yltrifluoromethanesulfonate (316 mg) MS [M+H⁺]=348.9.

Step 8.8-Methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline

Following GENERAL METHOD 2-1 for boronate ester formation using8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-yltrifluoromethanesulfonate (316 mg, 1.24 mmol) afforded8-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline(271 mg) MS [M+H⁺]=327.4.

Step 9:6-(8-Methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Following standard GENERAL METHOD 1-4 for Suzuki coupling using8-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline(104 mg, 0.32 mmol) and6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 90 mg, 0.32 mmol), afforded6-(8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(140 mg) MS [M+H⁺]=447.6.

Step 10:9-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5,6-dihydroimidazo[5,1-a]isoquinolin-8-ol

Following standard GENERAL METHOD 3-2 for methoxy deprotection, thetitle compound was afforded. MS [M+H⁺]=433.3, LCMS Rt=0.40 min [MethodQ]; ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.97 (d, J=1.26 Hz, 1H), 8.46(d, J=10.04 Hz, 1H), 8.21 (s, 1H), 7.98 (d, J=1.25 Hz, 1H), 7.85 (d,J=10.04 Hz, 1H), 7.10 (s, 1H), 5.08-5.35 (m, 1H), 4.50 (t, J=6.65 Hz,2H), 3.26-3.31 (m, 2H), 3.17 (s, 3H), 1.99-2.11 (m, 4H), 1.67 (s, 6H),1.57 (s, 6H).

Example 36-1 Synthesis of4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide

Step 1: 3-Bromo-4-methoxy-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide

To a 100 mL round bottom flask containing 3-bromo-4-methoxybenzoic acid(500 mg, 2.16 mmol) and DCM (5 mL) was added oxalyl chloride (0.23 mL,2.60 mmol) and DMF (0.1 mL, 0.13 mmol). The reaction mixture was stirredat RT for one hour and concentrated in vacuo. The resulting colorlessoil was taken up in DCM (2.5 mL) and added to a mixture of(1-methyl-1H-pyrazol-4-yl)methanamine (241 mg, 2.16 mmol), TEA (0.60 mL,4.33 mmol) and DCM (2.5 mL) at 0° C. The reaction mixture was stirred atRT for 0.5 hours then concentrated in vacuo. The crude material waspurified by silica gel chromatography (0-10% MeOH in DCM) to afford3-bromo-4-methoxy-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide (702 mg)MS [M+H⁺]=325.9.

Step 2:(2-Methoxy-5-(((1-methyl-1H-pyrazol-4-yl)methyl)carbamoyl)phenyl)boronicacid

Following GENERAL METHOD 2-1 for boronate ester formation using3-bromo-4-methoxy-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide (552 mg,1.70 mmol) afforded(2-methoxy-5-(((1-methyl-1H-pyrazol-4-yl)methyl)carbamoyl)phenyl)boronicacid (492 mg) MS [M+H⁺]=290.1.

Step 3:4-Methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide

Following standard GENERAL METHOD 1-4 for Suzuki coupling using(2-methoxy-5-(((1-methyl-1H-pyrazol-4-yl)methyl)carbamoyl)phenyl)boronicacid (613 mg, 2.12 mmol) and6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 300 mg, 1.06 mmol) afforded4-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide(522 mg) MS [M+H⁺]=492.6.

Step 4:4-Hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide

Following standard GENERAL METHOD 3-2 for methoxy deprotection, thetitle compound was prepared. MS [M+H⁺]=478.3, LCMS Rt=0.46 min [MethodQ]; ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.31 (d, J=2.26 Hz, 1H), 8.18(d, J=10.04 Hz, 1H), 7.78 (dd, J=8.66, 2.13 Hz, 1H), 7.61 (s, 1H), 7.50(s, 1H), 7.36 (d, J=10.04 Hz, 1H), 7.01 (d, J=8.53 Hz, 1H), 5.06-5.27(m, 1H), 4.45 (s, 2H), 3.87 (s, 3H), 3.03 (s, 3H), 1.68-1.77 (m, 2H),1.54-1.67 (m, 2H), 1.42 (s, 6H), 1.27 (s, 6H).

Example 37-1 Synthesis of4-(4-(hydroxymethyl)-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Step 1: (1-(3-Bromo-4-methoxyphenyl)-1H-pyrazol-3-yl)methanol

To a 100 mL round bottom flask was added copper (I) iodide (30.4 mg,0.16 mmol), 2-(2-pyridyl)benzimidazole (31.2 mg, 0.16 mmol), cesiumcarbonate (625 mg, 1.92 mmol) and DMF (5.3 mL). The reaction mixture washeated to 60° C. for 1 h then (1H-pyrazol-3-yl)methanol (235 mg, 2.40mmol) and 2-bromo-4-iodo-1-methoxybenzene (500 mg, 1.60 mmol) were addedand the mixture was heated at 100° C. for 18 hours. The reaction wascooled, diluted with EtOAc and filtered through celite. The filtrate wasconcentrated in vacuo and purified by silica gel chromatography (0-100%EtOAc in Hepane) to afford(1-(3-bromo-4-methoxyphenyl)-1H-pyrazol-3-yl)methanol (353 mg) MS[M+2H⁺]=285.0.

Step 2:(1-(4-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-3-yl)methanol

Following GENERAL METHOD 2-1 for boronate ester formation using(1-(3-bromo-4-methoxyphenyl)-1H-pyrazol-3-yl)methanol (353 mg, 1.25mmol) afforded(1-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-3-yl)methanol(412 mg) MS [M+H⁺]=331.2.

Step 3:(1-(4-Methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1H-pyrazol-4-yl)methanol

To a microwave vial was added(1-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-3-yl)methanol(254 mg, 0.77 mmol),6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 1-1, 145 mg, 0.51 mmol), potassium phosphate (435 mg, 2.05mmol), Pd₂(dba)₃ (46.9 mg, 0.05 mmol), and SPhos (21.1 mg, 0.05 mmol),followed by addition of 1,4-dioxane (1.3 mL)/H₂O (0.3 mL). The vial waspurged with N₂ for 5 minutes and the reaction mixture was heated at 100°C. in the microwave for 2 h. The reaction mixture was concentrated invacuo. The crude material was adjusted to pH 3 using 12 M HCl aqueoussolution and loaded onto an SCX column. The crude material was washedwith methanol then eluted with 2 N ammonia in methanol. Theproduct-containing fractions were concentrated to afford(1-(4-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1H-pyrazol-4-yl)methanol(231 mg) MS [M+H⁺]=451.3.

Step 4:2-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-4-yl)phenol

Following standard GENERAL METHOD 3-1 for methoxy deprotection, thetitle compound was prepared. MS [M+H⁺]=437.3, LCMS Rt=0.50 min [MethodQ]; ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.43 (d, J=0.50 Hz, 1H), 8.38(d, J=10.04 Hz, 1H), 8.19 (d, J=2.76 Hz, 1H), 7.69 (dd, J=8.78, 2.51 Hz,1H), 7.63 (s, 1H), 7.36 (d, J=10.04 Hz, 1H), 7.04 (d, J=8.78 Hz, 1H),4.87-5.13 (m, 2H), 4.45 (d, J=5.27 Hz, 2H), 2.97 (s, 3H), 1.36-1.67 (m,4H), 1.25 (s, 7H), 1.09 (s, 6H).

Example 38-1 Synthesis of5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol

Step 1: 3-Chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine

To 50 mL flask was added 2,2,6,6-tetramethyl-4-methylenepiperidine2,2,2-trifluoroacetate (1.1 g, 4.12 mmol) and 9-BBN (0.5 M in THF) (16.5mL, 8.23 mmol) and the reaction mixture was heated at 65° C. for 1 h.The reaction was cooled to RT and 3,5-dichloropyridazine (0.61 g, 4.12mmol), K₂CO₃ (1.7 g, 12.35 mmol), and PdCl₂(dppf).CH₂Cl₂ (0.17 g, 0.21mmol) in 1,4-dioxane (8.5 mL)/H₂O (1.7 mL) were added and heated at 60°C. overnight. The reaction mixture was cooled to RT, diluted with EtOAc,filtered through celite and concentrated in vacuo. The crude materialwas adjusted to pH 3 using 12 M HCl aqueous solution and loaded onto anSCX column. The crude material was washed with methanol then eluted with2 N ammonia in methanol. The product-containing fractions wereconcentrated to afford3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine (1.1 g)MS [M+H⁺]=268.2.

Step 2:3-Methoxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol

Following standard GENERAL METHOD 1-4 for Suzuki coupling usingtert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane(408 mg, 1.12 mmol) and3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine (200mg, 0.75 mmol) affords3-methoxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol(165 mg) MS [M+H⁺]=356.1.

Step 3:3-Methoxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenyltrifluoromethanesulfonate

To a solution of3-methoxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol(165 mg, 0.46 mmol) in DCM (2.8 mL) was added TEA (0.162 mL, 1.16 mmol)at RT. The reaction mixture was cooled to 0° C., followed by addition ofN-phenyltrifluoromethanesulfonimide (174 mg, 0.49 mmol). The reactionmixture was warmed to RT and stirred for 2 h. The reaction was quenchedwith aqueous sodium bicarbonate solution and extracted with DCM. Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo. The crude product was adjusted to pH 3 using 1 M HCl aqueoussolution and loaded on an SCX column, then washed with methanol andeluted with 2 N ammonia in methanol. The product fractions werecollected and dried to afford3-methoxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenyltrifluoromethanesulfonate (160 mg) MS [M+H⁺]=488.0.

Step 4:3-(2-Methoxy-4-(1H-pyrazol-4-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine

To a microwave vial was added3-methoxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenyltrifluoromethanesulfonate (160 mg, 0.33 mmol), 1H-pyrazol-4-ylboronicacid, (73.4 mg, 0.66 mmol), potassium phosphate (209 mg, 0.99 mmol),Pd₂(dba)₃ (30.1 mg, 0.03 mmol), and SPhos (26.9 mg, 0.06 mmol), followedby addition of 1,4-dioxane (2.6 mL)/H₂O (0.7 mL). The vial was purgedwith N₂ for 5 minutes and the reaction mixture was heated at 100° C. inthe microwave for 1 h. The reaction mixture was concentrated in vacuo.The crude material was adjusted to pH 3 using 1 M HCl aqueous solutionand loaded on an SCX column. The crude material was washed with methanolthen eluted with 2 N ammonia in methanol. The product-containingfractions were concentrated to afford3-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine(133 mg) MS [M+H⁺]=406.2.

Step 5:5-(1H-Pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol

Following standard GENERAL METHOD 3-2 for methoxy deprotection, thetitle compound was afforded. MS [M+H⁺]=392.4, LCMS Rt=0.45 min [MethodQ]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.65 (br. s., 1H), 13.05 (br. s.,1H), 8.47 (d, J=9.03 Hz, 1H), 8.18 (br. s., 2H), 8.01 (d, J=8.28 Hz,1H), 7.84 (d, J=9.03 Hz, 1H), 7.24-7.33 (m, 2H), 2.83 (d, J=7.03 Hz,2H), 2.20-2.37 (m, 1H), 1.44 (dd, J=12.55, 2.76 Hz, 2H), 1.08 (s, 6H),0.99 (s, 6H), 0.86 (t, J=12.42 Hz, 2H).

Example 39-1 Synthesis of6-(3-(benzyloxy)isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Step 1: 3-(Benzyloxy)-6-bromoisoquinoline

To a 25 mL round-bottomed flask containing 6-bromoisoquinolin-3-ol (500mg, 2.23 mmol) was added TEA (0.467 mL, 3.35 mmol) and benzyl bromide(0.319 mL, 2.68 mmol) in DMF (10 mL) to give a brown solution. Thereaction was heated to 80° C. overnight. After cooling to RT, thereaction mixture was concentrated in vacuo, and taken up in DCM andwater. The water was extracted with DCM (2×), and the combined organicfractions were washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purify by flash columnchromatography (10-30-50% EtOAc/Heptanes), providing the title compound(132 mg, 0.420 mmol, 19% yield). M+1=316.0. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.92 (s, 1H), 7.85 (d, J=1.25 Hz, 1H), 7.74 (d, J=8.78Hz, 1H), 7.31-7.52 (m, 6H), 6.99 (s, 1H), 5.48 (s, 2H).

Step 2:3-(Benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline

Following GENERAL METHOD 2-1 for boronate ester formation using3-(benzyloxy)-6-bromoisoquinoline (125 mg, 0.398 mmol) the titlecompound was prepared (115 mg, 0.398 mmol, 80% yield). M+1=362.3. ¹H NMR(400 MHz, CHLOROFORM-d) δ 8.98 (s, 1H), 8.20 (s, 1H), 7.87 (d, J=8.28Hz, 1H), 7.72 (dd, J=8.28, 1.00 Hz, 1H), 7.50-7.54 (m, 2H), 7.36-7.42(m, 2H), 7.30-7.35 (m, 1H), 7.12 (s, 1H), 5.48 (s, 2H), 1.40 (s, 12H).

Step 3:6-(3-(Benzyloxy)isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

The title compound (38 mg, 0.077 mmol, 49% yield) was prepared followingGENERAL METHOD 1-4 for Suzuki coupling from3-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(115 mg, 0.318 mmol) and Intermediate 1-1 (45 mg, 0.159 mmol). LCMSRt=0.61 min [Method Q]; MS (M+1)=482.4. ¹H NMR (400 MHz, METHANOL-d4) δppm 8.95 (s, 1H), 8.21 (s, 1H), 8.01-8.09 (m, 2H), 7.96 (d, J=9.79 Hz,1H), 7.49-7.54 (m, 2H), 7.36-7.42 (m, 2H), 7.30-7.35 (m, 1H), 7.23 (s,1H), 7.16 (d, J=9.79 Hz, 1H), 5.40 (s, 2H), 5.28 (t, J=11.67 Hz, 1H),3.00 (s, 3H), 1.67-1.73 (m, 2H), 1.56-1.65 (m, 2H), 1.41 (s, 6H), 1.26(s, 6H).

Example 39-2 Synthesis of6-(1-(benzyloxy)isoquinolin-7-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Step 1: 1-(Benzyloxy)-7-bromoisoquinoline

To a 25 mL round-bottom flask containing 7-bromoisoquinolin-1-ol (500mg, 2.23 mmol) was added TEA (0.467 mL, 3.35 mmol) and benzyl bromide(0.319 mL, 2.68 mmol) in DMF (10 mL) to give a brown solution. Thereaction was heated to 80° C. overnight. After cooling to RT, thereaction mixture was concentrated in vacuo, and taken up in DCM andwater. The aqueous layer was extracted with DCM (2×), and the combinedorganics fractions were washed with brine, dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purify by flash columnchromatography (10-30-50% EtOAc/Heptanes), providing the title compound(640 mg, 2.037 mmol, 91% yield). M+1=316.0. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.62 (d, J=2.01 Hz, 1H), 7.73 (dd, J=2.13, 8.41 Hz, 1H),7.39 (d, J=8.28 Hz, 1H), 7.28-7.36 (m, 5H), 7.11 (d, J=7.53 Hz, 1H),6.46 (d, J=7.28 Hz, 1H), 5.23 (s, 2H).

Step 2:1-(Benzyloxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline

Following GENERAL METHOD 2-1 for boronate ester formation using1-(benzyloxy)-7-bromoisoquinoline (250 mg, 0.796 mmol) afforded thetitle compound (207 mg, 0.573 mmol, 72% yield). M+1=362.2. ¹H NMR (400MHz, CHLOROFORM-d) δ 8.96 (s, 1H), 8.00 (dd, J=7.91, 1.13 Hz, 1H), 7.47(d, J=7.78 Hz, 1H), 7.27-7.34 (m, 5H), 7.11 (d, J=7.53 Hz, 1H), 6.46 (d,J=7.28 Hz, 1H), 5.23 (s, 2H), 1.36 (s, 12H).

Step 3:6-(1-(Benzyloxy)isoquinolin-7-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

The title compound (120 mg, 0.249 mmol, 94% yield) was preparedfollowing GENERAL METHOD 1-4 for Suzuki reaction from1-(benzyloxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(144 mg, 0.398 mmol) and (Intermediate 1-1, 75 mg, 0.265 mmol). LCMSRt=0.57 min [Method Q]; MS (M+1)=482.4. ¹H NMR (400 MHz, METHANOL-d4) δppm 8.81 (d, J=2.01 Hz, 1H), 8.39 (dd, J=8.41, 1.88 Hz, 1H), 7.99 (d,J=9.79 Hz, 1H), 7.76 (d, J=8.53 Hz, 1H), 7.72-7.74 (m, 1H), 7.46 (d,J=7.28 Hz, 1H), 7.26-7.37 (m, 5H), 7.24 (d, J=9.79 Hz, 1H), 6.76 (d,J=7.53 Hz, 1H), 5.29 (s, 2H), 3.01 (s, 3H), 1.71-1.78 (m, 2H), 1.61-1.70(m, 2H), 1.44 (s, 6H), 1.29 (s, 6H).

Example 40-1 Synthesis of3-fluoro-5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenolhydrochloride salt

Following GENERAL METHOD 1-6 for Suzuki cross-coupling,5-bromo-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(Intermediate 8-1) and (2-methoxypyridin-4-yl)boronic acid were reactedand the crude product was purified via reverse phase preparative HPLC(10% CH₃CN to 30% in H₂O). After salt formation,3-fluoro-5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenolhydrochloride salt was afforded as a yellow solid (5.7 mg). LCMS Rt=0.56min [Method Q]; [M+H]: 466.4; ¹H NMR (400 MHz, MeOD) δ 8.25 (d, J=5.5Hz, 1H), 8.20 (d, J=10.0 Hz, 1H), 7.71 (d, J=10.0 Hz, 1H), 7.30 (dd,J=5.5, 1.5 Hz, 1H), 7.21 (dd, J=12.0, 1.5 Hz, 1H), 7.21 (s, 1H), 7.13(d, J=1.0 Hz, 1H), 5.38-5.22 (m, 1H), 4.01 (s, 3H), 3.14 (s, 3H), 2.03(d, J=8.5 Hz, 4H), 1.67 (s, 6H), 1.56 (s, 6H).

Example 40-2 Synthesis of4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-2(1H)-onehydrochloride salt

3-Fluoro-5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenolhydrochloride salt (Example 40-1, 10 mg, 0.02 mmol) and pyridinehydrochloride (50 mg, 0.43 mmol) were heated at 170° C. for 15 minutesin a Biotage® Initiator microwave reactor. The reaction mixture wasdiluted with MeOH/DMSO, and purified via reverse phase preparative HPLC(10 to 45% acetonitrile in water, 0.1% trifluoroacetic acid asmodifier). The appropriate fractions containing product were free basedby catch and release using SiliaBond Propylsulphonic Acid® (4 eq,methanol as eluent and a 2 N ammonia solution in MeOH to release thematerial). The solvent was concentrated in vacuo and the resulting solidwas suspended in CH₃CN/H₂O (3/1 mL). 1 M aqueous HCl (3 equivalents) wasadded and solvent was concentrated in vacuo to afford the title compoundas a yellow solid (3 mg, 26%). LCMS Rt=0.47 min [Method Q]; [M+H]:452.3; ¹H NMR (400 MHz, MeOD) δ 8.28 (d, J=10.0 Hz, 1H), 8.07 (d, J=10.0Hz, 1H), 7.69 (d, J=6.5 Hz, 1H), 7.25 (dd, J=11.0, 1.5 Hz, 1H), 7.19 (s,1H), 6.89 (s, 1H), 6.85 (dd, J=6.5, 1.5 Hz, 1H), 5.07 (bs, 1H), 3.21 (s,3H), 2.20-2.00 (m, 4H), 1.66 (s, 6H), 1.59 (s, 6H).

Example 40-3 Synthesis of4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-onehydrochloride salt

Following GENERAL METHOD 1-6 for Suzuki cross-coupling,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneand5-bromo-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(Intermediate 8-1) were reacted and the crude product was purified viareverse phase preparative HPLC (10% CH₃CN to 30% in H₂O). After saltformation,4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-onehydrochloride salt was afforded as a yellow solid (10 mg, 12%). LCMSRt=0.49 min [Method Q]; [M+H]: 466.3; ¹H NMR (400 MHz, MeOD) δ 8.22 (d,J=10.0 Hz, 1H), 7.86-7.73 (m, 2H), 7.24-7.13 (m, 2H), 6.82 (d, J=2.0 Hz,1H), 6.72 (dd, J=7.0, 2.0 Hz, 1H), 5.30-5.15 (m, 1H), 3.64 (s, 3H), 3.16(s, 3H), 2.04 (d, J=8.0 Hz, 4H), 1.67 (s, 6H), 1.57 (s, 6H).

Example 40-4 Synthesis of5-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-onehydrochloride salt

Following GENERAL METHOD 1-6 for Suzuki cross-coupling,5-bromo-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenoland1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onewere reacted and the crude product was purified via reverse phasepreparative HPLC (10% CH₃CN to 30% in H₂O). After salt formation,5-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-onehydrochloride salt was afforded as a yellow solid (8.0 mg, 11%). LCMSRt=0.49 min [Method Q]; [M+H]: 466.3; ¹H NMR (400 MHz, MeOD) δ 8.28 (d,J=10.0 Hz, 1H), 8.08 (d, J=10.0 Hz, 1H), 7.83 (d, J=7.0 Hz, 1H), 7.23(dd, J=11.0, 1.5 Hz, 1H), 7.17 (s, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.75(dd, J=7.0, 2.0 Hz, 1H), 5.06 (bs, 1H), 3.66 (s, 3H), 3.21 (s, 3H),2.19-2.01 (m, 4H), 1.66 (s, 6H), 1.59 (s, 6H).

Example 40-5 Synthesis of3-fluoro-5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolhydrochloride salt

Step 1:3-(2-Fluoro-4-methoxyphenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine

Intermediate 1-3 (2.14 g, 7.92 mmol), (2-fluoro-4-methoxyphenyl)boronicacid (2.02 g, 11.9 mmol), and a 0.5 M aqueous solution of K₃PO₄ (32 ml,16 mmol) were added to a microwave vial. 2nd Generation XPhosPrecatalyst (0.19 g, 0.24 mmol) was added to the mixture followed byaddition of THF (16 mL). The reaction mixture was sealed and stirred atRT for 2 h then extracted with EtOAc (3×). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo to provide3-(2-fluoro-4-methoxyphenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazineas a brown solid (2.85 g, 90%). [M+H]: 360.3; ¹H NMR (400 MHz, MeOD) δ7.90 (dd, J=9.5, 2.5 Hz, 1H), 7.81 (t, J=9.0 Hz, 1H), 7.18 (d, J=9.5 Hz,1H), 6.94 (dd, J=9.0, 2.5 Hz, 1H), 6.88 (dd, J=13.0, 2.5 Hz, 1H), 5.79(tt, J=11.0, 4.0 Hz, 1H), 3.89 (s, 3H), 2.24 (dd, J=12.0, 4.0 Hz, 2H),1.43 (t, J=12.0 Hz, 2H), 1.37 (s, 6H), 1.26 (s, 6H).

Step 2:3-Fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol

3-(2-Fluoro-4-methoxyphenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine(1.08 g, 3.00 mmol) was dissolved in CH₂Cl₂ (15 mL) and a 1 M solutionof BBr₃ in CH₂Cl₂ (7.5 mL, 7.5 mmol) was added dropwise. The reactionmixture was stirred at RT overnight, then diluted with CH₂Cl₂ and a pH 4buffered aqueous solution. The aqueous phase was washed with 3:1chloroform/propan-2-ol (2×), then basified to pH 8 with saturatedNaHCO₃. The aqueous phase was extracted with 3:1 chloroform/propan-2-ol(4×). The combined organic phases were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure.3-Fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolwas afforded as a brown solid (0.59 g, 52%). [M+H]: 346.4; ¹H NMR (400MHz, MeOD) δ 7.88 (dd, J=9.0, 2.2 Hz, 1H), 7.69 (t, J=9.0 Hz, 1H), 7.16(d, J=9.0 Hz, 1H), 6.76 (dd, J=9.0, 2.0 Hz, 1H), 6.65 (dd, J=13.0, 2.0Hz, 1H), 5.78 (tt, J=11.0, 4.0 Hz, 1H), 2.26 (dd, J=12.5, 4.0 Hz, 2H),1.47 (t, J=12.0 Hz, 2H), 1.39 (s, 6H), 1.29 (s, 6H).

Step 3:3-Fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyltrifluoromethanesulfonate

3-Fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol(0.70 g, 2.03 mmol), N-phenylbis(trifluoromethane-sulfonimide) (0.72 g,2.03 mmol), K₂CO₃ (0.84 g, 6.08 mmol) and THF (10 mL) were mixed in amicrowave vial. The reaction mixture was heated to 120° C. for 10minutes in a Biotage® Initiator microwave reactor. The volatiles wereremoved under vacuum. A 1 M aqueous solution of NaOH was added and theaqueous phase was extracted with DCM (2×). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated todryness in vacuo. The crude material was purified by flash columnchromatography using silica gel (elution gradient of 10-50% (3/1)EtOAc/2 N NH₃ in EtOH, in heptane) to give3-fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyltrifluoromethanesulfonate as a red gray solid (0.63 g, 66%). [M+H]:478.2; ¹H NMR (400 MHz, MeOD) δ 8.09 (t, J=8.6 Hz, 1H), 7.99 (dd, J=9.2,2.4 Hz, 1H), 7.50 (dd, J=10.6, 2.4 Hz, 1H), 7.45 (dd, J=8.6, 2.4 Hz,1H), 7.24 (d, J=9.5 Hz, 1H), 5.82 (tt, J=11.2, 4.2 Hz, 1H), 2.24 (dd,J=12.6, 4.1 Hz, 2H), 1.43 (t, J=11.7 Hz, 2H), 1.36 (s, 6H), 1.25 (s,6H).

Step 4:3-Fluoro-5-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyltrifluoromethanesulfonate

3-Fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyltrifluoromethanesulfonate (0.48 g, 1.01 mmol), PhI(OAc)₂ (0.46 g, 1.41mmol), and Pd(OAc)₂(68 mg, 0.10 mmol) were dissolved in a mixture ofacetic acid (4 mL) and acetic anhydride (4 mL). The mixture was stirredat 80° C. for 3 h. The crude reaction was purified by catch and releaseusing SiliaBond Propylsulfonic Acid® (5 eq, CH₃CN as eluent and a 2 Nammonia solution in MeOH to release the material). The solvent wasconcentrated in vacuo and3-fluoro-5-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyltrifluoromethanesulfonate was afforded as a green solid (0.50 g, 100%).[M+H]: 494.3; ¹H NMR (400 MHz, MeOD) δ 8.09 (t, J=8.5 Hz, 1H), 7.99 (dd,J=9.5, 2.5 Hz, 1H), 7.50 (dd, J=10.5, 2.5 Hz, 1H), 7.45 (dd, J=8.5, 2.5Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 5.82 (tt, J=11.0, 4.0 Hz, 1H), 2.24(dd, J=12.5, 4.0 Hz, 2H), 1.43 (t, J=12.0 Hz, 2H), 1.36 (s, 6H), 1.25(s, 6H).

Step 5:3-Fluoro-5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolhydrochloride salt

Following the representative procedure GENERAL METHOD 1-6 for Suzukicross-coupling,3-fluoro-5-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyltrifluoromethanesulfonate and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylatewere reacted and the crude product was purified via reverse phasepreparative HPLC (10% CH₃CN to 30% in H₂O). After salt formation, thehydrochloride salt of3-fluoro-5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolhydrate was afforded as a yellow solid (49 mg, 25%). LCMS Rt=0.49 min;[M+H]: 412.3; ¹H NMR (400 MHz, MeOD) δ 8.51 (d, J=9.5 Hz, 1H), 8.26 (s,2H), 7.87 (d, J=9.5 Hz, 1H), 7.21 (dd, J=12.0, 1.5 Hz, 1H), 7.16 (s,1H), 5.77 (tt, J=10.5, 4.0 Hz, 1H), 2.52 (dd, J=14.0, 4.0 Hz, 2H), 1.93(dd, J=14.0, 10.5 Hz, 2H), 1.64 (s, 6H), 1.59 (s, 6H).

Example 40-6 Synthesis of5-chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenolhydrochloride salt

Step 1:6-(4-Chloro-2-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

(4-Chloro-2-fluorophenyl)boronic acid (4.29 g, 24.6 mmol), Intermediate1-1 (6.63 g, 23.4 mmol) and Na₂CO₃ (7.45 g, 70.3 mmol) were degassed for10 minutes with N₂, then PdCl₂(dppf)CH₂Cl₂ (0.96 g, 1.17 mmol) wasadded. The reaction mixture was heated at 90° C. for 2 h. The reactionmixture was concentrated in vacuo then CH₂Cl₂ and 1 M HCl were added.The aqueous phase was washed with CH₂Cl₂, then basified to pH 14 with a6 M NaOH solution. The aqueous phase was then extracted with CH₂Cl₂(3×). The combined organic phases were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford6-(4-chloro-2-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineas a brown solid (8.40 g, 95%). [M+H]: 377.2; ¹H NMR (400 MHz, MeOD) δ7.87 (t, J=8.5 Hz, 1H), 7.76 (dd, J=9.5, 2.4 Hz, 1H), 7.32-7.40 (m, 2H),7.17 (d, J=9.5 Hz, 1H), 5.13-5.36 (m, 1H), 1.69 (dd, J=12.5, 3.5 Hz,2H), 1.57 (t, J=12.5 Hz, 2H), 1.38 (s, 6H), 1.23 (s, 6H).

Step 2:5-Chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol.Hydrochloride salt

6-(4-Chloro-2-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(50 mg, 0.13 mmol), PhI(OAc)₂(60 mg, 0.19 mmol), and Pd(OAc)₂(8.9 mg,0.013 mmol) were dissolved in a mixture of acetic acid (0.6 mL) andacetic anhydride (0.6 mL). The mixture was stirred at 40° C. overnight.A solution of sodium thiosulfate was added and the mixture was stirredfor 8 days at RT. A solution of potassium carbonate was added and thereaction pH was adjusted to 10. The aqueous phase was extracted (2×)with dichloromethane and methanol (9:1). The combined organic phaseswere dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude material was purified via reverse phasepreparative HPLC (10 to 30% acetonitrile in water, 0.1% trifluoroaceticacid as modifier). The appropriate fractions containing product werefree based by catch and release using SiliaBond Propylsulphonic Acid® (4eq, CH₃CN as eluent and a 2 N ammonia solution in MeOH to release thematerial). The solvent was concentrated in vacuo and the resulting solidwas suspended in CH₃CN/H₂O (3/1 mL). 1 M aqueous HCl (3 equivalents) wasadded, and the volatiles were concentrated in vacuo to afford thehydrochloride salt of5-chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenolas a yellow solid (19 mg, 33%). LCMS Rt=0.57 min [Method Q]; [M+H]:393.2; ¹H NMR (400 MHz, MeOD) δ 8.21 (d, J=10.0 Hz, 1H), 7.99 (d, J=10.0Hz, 1H), 6.99 (dd, J=10.0, 2.0 Hz, 1H), 6.94 (t, J=2.0 Hz, 1H), 5.09(bs, 1H), 3.18 (s, 3H), 1.98-2.12 (m, 4H), 1.65 (s, 6H), 1.57 (s, 6H).

Example 40-7 Synthesis of3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenolhydrochloride salt

5-Chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(Example 40-6, 0.32 g, 0.82 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(1.00 g, 3.40 mmol), and Cs₂CO₃ (5.52 g, 26.0 mmol) were added to amicrowave vial. XPhos Precatalyst (60 mg, 0.08 mmol) was then added tothe mixture followed by dioxane (5 mL) and water (0.9 mL). The reactionmixture was sealed and stirred at 130° C. for 2 h in a Biotage®Initiator microwave reactor. The reaction mixture was filtered throughcelite and the filter cake was washed with methanol. The filtrate wasconcentrated in vacuo. The crude product was purified via reverse phasepreparative HPLC (10 to 45% acetonitrile in water, 0.1% trifluoroaceticacid as modifier). The appropriate fractions containing product werefree based by catch and release using SiliaBond Propylsulphonic Acid® (4eq, methanol as eluent and a 2 N ammonia solution in MeOH to release thematerial). The solvent was concentrated in vacuo and the resulting solidwas dissolved in MeOH. SiliaMetS® DMT (6 eq.) was added and the mixturewas shaken for 18 h. The solid was filtered and the filtrate wasconcentrated in vacuo. The resulting solid was suspended in CH₃CN/H₂O(6/2 mL). 1 M HCl aqueous (3 equivalents) was added and volatiles wereconcentrated in vacuo to provide the hydrochloride salt of3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenolas a yellow solid (47 mg). LCMS Rt=0.48 min [Method Q]; [M+H]: 425.3; ¹HNMR (400 MHz, MeOD) δ 8.25-8.32 (m, 1H), 8.14 (s, 2H), 8.04 (d, J=10.0Hz, 1H), 7.19 (dd, J=11.5, 1.5 Hz, 1H), 7.11 (s, 1H), 5.10 (bs, 1H),3.19 (s, 3H), 1.91-2.24 (m, 4H), 1.66 (s, 6H), 1.57 (s, 6H).

Example 40-8 Synthesis of3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenolhydrochloride salt

Step 1:6-(2-Fluoro-6-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Following GENERAL METHOD 1-6 for Suzuki cross-coupling, a mixture of6-(4-bromo-2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine,4-bromo-6-(2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 8-1, Step 2, 0.10 g, 0.22 mmol, total amount of the 2regioisomers) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.14 g, 0.67 mmol) were reacted. The crude product was purified bycolumn chromatography using silica gel and a gradient elution of 1-15% 7N ammonia in MeOH, in CH₂Cl₂. An inseparable mixture of the desiredproduct(6-(2-fluoro-6-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6tetramethylpiperidin-4-yl)pyridazin-3-amine) and6-(2-fluoro-6-methoxyphenyl)-N-methyl-4-(1-methyl-1H-pyrazol-4-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-aminewas afforded as a colorless solid (80 mg, 80%). [M+H]: 453.4.

Step 2:3-Fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenolhydrochloride salt

A mixture of6-(2-fluoro-6-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amineand6-(2-fluoro-6-methoxyphenyl)-N-methyl-4-(1-methyl-1H-pyrazol-4-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(0.03 g, 0.07 mmol, total amount of the 2 regioisomers) was dissolved inCH₂Cl₂ (0.2 M). A 1 M solution of BBr₃ in CH₂Cl₂ (0.3 mL, 3.5 mmol) wasrapidly added. The reaction mixture was stirred for 3 h. MeOH was addedto the reaction at 0° C. then the solvent was concentrated under reducedpressure. The crude material was purified via reverse phase preparativeHPLC (15 to 45% acetonitrile in water, 5 mM ammonium hydroxide asmodifier). The solvent was concentrated in vacuo and the resulting solidwas suspended in CH₃CN/H₂O (4/1 mL). 1 M aqueous HCl (3 equivalents) wasadded and the volatiles were concentrated in vacuo to afford thehydrochloride salt of 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenolas a yellow solid (5 mg, 15%). LCMS Rt=0.50 min [Method Q]; [M+H]:439.4; ¹H NMR (400 MHz, DMSO) δ 9.20 (d, J=12.0 Hz, 1H), 8.29 (d, J=12.0Hz, 1H), 8.23 (s, 1H), 8.04 (d, J=9.5 Hz, 1H), 7.92 (s, 1H), 7.79 (bs,1H), 7.09 (dd, J=12.0, 1.5 Hz, 1H), 7.04 (s, 1H), 4.92 (bs, 1H), 3.88(s, 3H), 3.03 (s, 3H), 2.05 (t, J=13.0 Hz, 2H), 1.81 (dd, J=13.0, 3.5Hz, 2H), 1.53 (s, 6H), 1.49 (s, 6H).

Example 41-1 Synthesis of5-(5-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Following GENERAL METHOD 1-3 for Suzuki Coupling, to a 25 mL microwavevial, was added3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (94mg, 0.400 mmol),3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyltrifluoromethanesulfonate (Intermediate 9-2, 105 mg, 0.2 mmol), sodiumbicarbonate (50.4 mg, 0.600 mmol) and Pd(PPh₃)₄ (11.56 mg, 10.00 μmol),followed by dioxane (2 mL) and water (0.5 mL). The reaction mixture waspurged with N₂ for 10 minutes, and heated in a microwave at 100° C. for1 h, then diluted with EtOAc and filtered through celite. The filtratewas acidified to pH ˜3 with 1N HCl, and loaded onto an SCX column. Thecolumn was washed with MeOH, and eluted with 2N NH₃ in MeOH. Afterconcentration, the residue was purified by preparative HPLC to provide5-(5-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(55 mg, 0.120 mmol, 60% yield), LCMS: Rt=0.50 min [Method Q]; MS(M+1)=448.4; ¹H NMR (METHANOL-d₄) δ 8.17 (d, J=5.1 Hz, 1H), 8.11 (d,J=9.1 Hz, 1H), 7.85 (d, J=7.1 Hz, 1H), 7.22-7.33 (m, 4H), 7.06 (s, 1H),5.10 (m, 1H), 3.97 (s, 3H), 3.03 (s, 3H), 1.74 (dd, J=12.6, 3.0 Hz, 2H),1.59 (t, J=12.4 Hz, 2H), 1.42 (s, 6H), 1.26 (s, 6H).

The following compounds were prepared using similar procedures as inExamples 41—from Intermediates 1-1, 1-3 or Example 32-1, Step 4, andgeneral methods as outlined in the GENERAL METHOD section.

LCMS Example Structure ¹H NMR, 400 MHz Method Q 41-2 

(METHANOL-d₄) δ 7.98 (d, J = 9.6 Hz, 1H), 7.86 (dd, J = 9.3, 2.8 Hz,1H), 7.69 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 10.1 Hz, 1H),6.99 (d, J = 2.0 Hz, 2H), 6.57 (d, J = 9.6 Hz, 1H), 4.97 (m, 1H), 2.93(s, 3H), 1.64 (dd, J = 12.6, 3.5 Hz, 2H), 1.49 (t, J = 12.6 Hz, 2H),1.32 (s, 6H), 1.16 (s, 6H) Rt = 0.48 min M + 1 = 434.3 41-3 

(METHANOL-d₄) δ 8.01 (d, J = 9.6 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.39(d, J = 7.1 Hz, 1H), 7.11-7.21 (m, 3H), 6.71 (d, J = 1.0 Hz, 1H), 6.64(dd, J = 6.8, 1.8 Hz, 1H), 5.02 (m, 1H), 2.93 (s, 3H), 1.66 (dd, J =12.6, 3.0 Hz, 2H), 1.52 (t, J = 12.4 Hz, 2H), 1.34 (s, 6H), 1.18 (s, 6H)Rt = 0.49 min M + 1 = 434.3 41-4 

(METHANOL-d₄) δ 8.42 (s, 1H), 8.10 (br. s., 1H), 7.97 (d, J = 8.1 Hz,1H), 7.77-7.86 (m, 1H), 7.28 (d, J = 7.1 Hz, 1H), 7.19 (s, 2H), 6.89 (d,J = 8.1 Hz, 1H), 5.06 (m, 1H), 3.97 (s, 3H), 3.02 (s, 3H), 1.72 (dd, J =12.1, 3.0 Hz, 2H), 1.58 (t, J = 12.4 Hz, 2H), 1.41 (s, 6H), 1.25 (s, 6H)Rt = 0.59 min M + 1 = 448.4 41-5 

(METHANOL-d₄) δ 8.18-8.24 (m, 1H), 8.05 (d, J = 9.6 Hz, 1H), 7.90 (br.s., 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 10.1 Hz, 1H), 7.11 (d, J= 2.0 Hz, 1H), 7.04- 7.09 (m, 1H), 5.13 (m, 1H), 3.02 (s, 3H), 1.77 (dd,J = 12.9, 3.3 Hz, 2H), 1.65 (t, J = 12.4 Hz, 2H), 1.45 (s, 6H),1.27-1.33 (s, 6H) Rt = 0.54 min M + 1 = 502.3 41-6 

(DMSO-d6) δ 13.90 (br. s., 1H), 8.21-8.29 (m, 2H), 7.85-7.95 (m, 2H),7.36 (d, J = 10.1 Hz, 1H), 7.17-7.22 (m, 1H), 7.15 (dd, J = 8.3, 1.8 Hz,1H), 6.48 (d, J = 9.6 Hz, 1H), 4.96 (m, 1H), 3.53 (s, 3H), 2.96 (s, 3H),1.53 (dd, J = 11.9, 3.3 Hz, 2H), 1.44 (t, J = 12.1 Hz, 2H), 1.26 (s,6H), 1.10 (s, 6H) Rt = 0.50 min M + 1 = 448.4 41-7 

(METHANOL-d₄) δ 8.16 (d, J = 10.1 Hz, 1H), 7.87-7.93 (m, 1H), 7.74 (d, J= 7.1 Hz, 1H), 7.34 (d, J = 10.1 Hz, 1H), 7.25-7.30 (m, 2H), 6.84 (d, J= 2.0 Hz, 1H), 6.76 (dd, J = 7.1, 2.0 Hz, 1H), 5.17 (m, 1H), 3.63 (s,3H), 3.04 (s, 3H), 1.76 (dd, J = 12.6, 3.0 Hz, 2H), 1.66 (t, J = 12.6Hz, 2H), 1.45 (s, 6H), 1.29 (s, 6H) Rt = 0.51 min M + 1 = 448.4 41-8 

(METHANOL-d₄) δ 8.17 (d, J = 5.1 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 7.85(d, J = 7.1 Hz, 1H), 7.22-7.33 (m, 4H), 7.06 (s, 1H), 5.10 (m, 1H), 3.97(s, 3H), 3.03 (s, 3H), 1.74 (dd, J = 12.6, 3.0 Hz, 2H), 1.59 (t, J =12.4 Hz, 2H), 1.42 (s, 6H), 1.26 (s, 6H) Rt = 0.60 min M + 1 = 448.441-9 

(DMSO-d₆) δ 12.87 (br. s., 1H), 11.64 (br. s., 1H), 8.45 (d, J = 9.6 Hz,1H), 8.04 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 6.6 Hz, 1H), 7.41 (d, J =9.6 Hz, 1H), 7.26-7.33 (m, 1H), 6.62 (d, J = 1.0 Hz, 1H), 6.54 (d, J =7.1 Hz, 1H), 5.69 (m, 1H), 2.13 (d, J = 9.1 Hz, 2H), 1.31- 1.42 (m, 2H),1.27 (s., 6H), 1.15 (s., 6H) Rt = 0.45 min M + 1 = 421.4 41-10

(DMSO-d₆) δ 13.80 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 9.6Hz, 1H), 7.89 (dt, J = 8.8, 2.1 Hz, 2H), 7.36 (d, J = 10.1 Hz, 1H),7.16-7.23 (m, 2H), 6.73 (d, J = 9.1 Hz, 1H), 4.95 (m, 1H), 3.08 (s, 6H),2.96 (s, 3H), 1.54 (dd, J = 12.1, 3.5 Hz, 2H), 1.44 (t, J = 12.1 Hz,2H), 1.26 (s, 6H), 1.10 (s, 6H) Rt = 0.44 min M + 1 = 461.5 41-11

(CHLOROFORM-d) δ 8.24 (d, J = 9.6 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H),7.64 (d, J = 7.1 Hz, 1H), 7.14-7.25 (m, 3H), 6.73 (s, 1H), 6.65 (d, J =6.6 Hz, 1H), 5.67 (m, 1H), 3.52 (s, 3H), 2.16 (dd, J = 12.6, 3.5 Hz,2H), 1.37 (t, J = 11.6 Hz, 2H), 1.30 (s, 6H), 1.18 (s, 6H) Rt = 0.47 minM + 1 = 435.4 41-12

(METHANOL-d₄) δ 9.15 (s, 1H), 9.08 (s, 2H), 8.11 (d, J = 10.1 Hz, 1H),7.90 (d, J = 8.1 Hz, 1H), 7.23-7.33 (m, 3H), 5.12 (m, 1H), 3.03 (s, 3H),1.76 (dd, J = 12.6, 3.5 Hz, 2H), 1.61 (t, J = 12.4 Hz, 2H), 1.43 (s,6H), 1.28 (s, 6H) Rt = 0.47 min M + 1 = 419.5 41-13

(METHANOL-d₄) δ 8.14 (d, J = 1.5 Hz, 1H), 8.03 (d, J = 10.1 Hz, 1H),7.96 (d, J = 2.0 Hz, 1H), 7.73-7.78 (m, 1H), 7.35 (t, J = 2.0 Hz, 1H),7.22 (d, J = 10.1 Hz, 1H), 7.08-7.13 (m, 2H), 5.06 (m, 1H), 2.92 (s,3H), 1.62-1.69 (m, 2H), 1.51-1.60 (m, 2H), 1.35 (s, 6H), 1.19 (s, 6H) Rt= 0.44 min M + 1 = 434.4 41-14

(METHANOL-d₄) δ 8.04 (d, J = 9.6 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.58(d, J = 7.1 Hz, 1H), 7.22 (d, J = 10.1 Hz, 1H), 7.12- 7.17 (m, 2H), 6.70(d, J = 2.0 Hz, 1H), 6.62 (dd, J = 7.1, 2.0 Hz, 1H), 5.03 (m, 1H),3.27-3.33 (m, 1H), 2.92 (s, 3H), 1.62 (dd, J = 12.6, 3.0 Hz, 2H), 1.51(t, J = 12.4 Hz, 2H), 1.31 (s, 6H), 1.16 (s, 6H), 1.01-1.09 (m, 2H),0.82-0.90 (m, 2H) Rt = 0.49 min M + 1 = 474.4 41-15

(METHANOL-d₄) δ 8.06 (d, J = 9.6 Hz, 1H), 7.67-7.72 (m, 1H), 7.27 (d, J= 10.1 Hz, 1H), 7.03 (dd, J = 8.3, 1.8 Hz, 1H), 7.00 (d, J = 1.5 Hz,1H), 6.23- 6.29 (m, 1H), 5.05 (m, 1H), 3.51 (q, J = 2.5 Hz, 2H), 3.09(t, J = 5.8 Hz, 2H), 3.00 (s, 3H), 2.48-2.56 (m, 2H), 1.69 (dd, J =12.6, 3.5 Hz, 2H), 1.58 (t, J = 12.4 Hz, 2H), 1.40 (s, 6H), 1.25 (s, 6H)Rt = 0.37 min M + 1 = 422.6 41-16

(METHANOL-d₄) δ 8.07 (d, J = 10.1 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H),7.29 (d, J = 10.1 Hz, 1H), 7.08 (dd, J = 8.3, 1.8 Hz, 1H), 7.01 (d, J =2.0 Hz, 1H), 6.26-6.32 (m, 1H), 5.07 (m, 1H), 3.02 (s, 3H), 2.69-2.76(m, 2H), 2.52-2.60 (m, 2H), 2.00-2.12 (m, 2H), 1.72 (dd, J = 12.6, 3.5Hz, 2H), 1.60 (t, J = 12.4 Hz, 2H), 1.42 (s, 6H), 1.26 (s, 6H) Rt = 0.60min M + 1 = 407.3 41-17

(METHANOL-d₄) δ 8.13 (d, J = 10.1 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H),7.36 (d, J = 9.6 Hz, 1H), 7.07 (dd, J = 8.3, 1.8 Hz, 1H), 7.04 (d, J =1.5 Hz, 1H), 6.28 (br. s., 1H), 5.33-5.46 (m, 1H), 4.31- 4.37 (m, 2H),3.95 (t, J = 5.3 Hz, 2H), 3.05 (s, 3H), 2.55 (d, J = 2.0 Hz, 2H),2.00-2.07 (m, 2H), 1.91-2.00 (m, 2H), 1.67 (s, 6H), 1.55 (s, 6H) Rt =0.52 min M + 1 = 423.3 41-18

(METHANOL-d₄) δ 8.40 (d, J = 7.1 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H),7.75-7.84 (m, 3H), 7.59 (s, 1H), 7.26-7.34 (m, 2H), 7.19- 7.25 (m, 2H),5.05 (m, 1H), 3.01 (s, 3H), 1.73 (dd, J = 12.6, 3.5 Hz, 2H), 1.56 (t, J= 12.4 Hz, 2H), 1.41 (s, 6H), 1.25 (s, 6H) Rt = 0.40 min M + 1 = 457.441-19

(METHANOL-d₄) δ 8.39 (d, J = 7.1 Hz, 1H), 8.02 (d, J = 10.1 Hz, 1H),7.73-7.80 (m, 3H), 7.58 (d, J = 1.5 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H),7.26 (dd, J = 8.1, 2.0 Hz, 1H), 7.17-7.23 (m, 2H), 5.02 (m, 1H), 2.99(s, 3H), 1.70 (dd, J = 12.6, 3.5 Hz, 2H), 1.53 (t, J = 12.6 Hz, 2H),1.39 (s, 6H), 1.23 (s, 6H) Rt = 0.41 min M + 1 = 457.3 41-20

(METHANOL-d₄) δ 8.47 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 10.1 Hz, 1H),7.91 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.52-7.59 (m, 1H), 7.29-7.39 (m,3H), 5.12 (t, J = 12.1 Hz, 1H), 3.04 (s, 3H), 2.63 (s, 3H), 1.67-1.77(m, 2H), 1.53-1.66 (m, 2H), 1.41 (s, 6H), 1.25 (s, 6H) Rt = 0.42 min M +1 = 432.2

Example 42-1 Synthesis of5-(1H-imidazol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Step 1:6-(4-(1H-Imidazol-2-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a microwave vial was added6-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 9-3, 100 mg, 0.21 mmol), 2-bromo-1H-imidazole (61.2 mg,0.42 mmol), Na₂CO₃ (44 mg, 0.42 mmol), and Pd(PPh₃)₂Cl₂ (14 mg, 0.02mmol), followed by DME (1 mL)/EtOH 0.25 mL)/(H₂O (0.25 mL). The vial waspurged with N₂ for 10 min and the reaction mixture was heated at 150° C.in a microwave reactor for 20 min. The reaction mixture was filteredthrough celite and the filter cake was washed with EtOAc. The filtratewas concentrated in vacuo to give the crude product which was purifiedby silica gel chromotography (5%-15% MeOH/DCM) to afford6-(4-(1H-imidazol-2-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(40 mg, MS: 421.3 [M+H⁺]).

Step 2:5-(1H-Imidazol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Following GENERAL METHOD 3-1 for methoxy deprotection using thiophenol,6-(4-(1H-imidazol-2-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(40 mg, 0.1 mmol) was treated with thiophenol (0.01 mL, 0.11 mmol) andK₂CO₃(13 mg, 0.1 mmol) in NMP (2 mL) for 30 min at 190° C. to afford5-(1H-imidazol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenolas pale yellow powder (6 mg). MS: 407.4 [M+H⁺]; LCMS Rt=0.40 min [MethodQ]; ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.00 (d, J=10.11 Hz, 1H),7.68-7.78 (m, 1H), 7.32-7.41 (m, 2H), 7.19 (d, J=10.11 Hz, 1H), 7.05 (s,2H), 4.96 (br. s., 1H), 2.90 (s, 3H), 1.58 (dd, J=12.38, 3.28 Hz, 2H),1.46 (t, J=12.38 Hz, 2H), 1.28 (s, 6H), 1.12 (s, 6H).

Example 42-2 Synthesis of5-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Step 1: 4-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

To a mixture of 4-bromo-1H-imidazole (1.0 g, 6.8 mmol) in THF (15 mL)was added NaH (327 mg, 8.16 mmol) at 0° C. The mixture was stirred at 0°C. to RT for 0.5 h. SEMCl (1.45 mL, 8.16 mmol) was added dropwise andthe reaction mixture was stirred at RT for 2 h. The reaction mixture wasquenched with water and extracted with DCM. The organic layer was dried(Na₂SO₄), filtered and concentrated in vacuo to give the crude productwhich was purified by silica gel chromotography (10-100% EtOAc/Heptane,then 0-15% MeOH/DCM) to afford4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.36 g, MS:279.3 [M+H⁺]).

Step 2:6-(2-Methoxy-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a microwave vial was added6-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 9-3, 50 mg, 0.10 mmol),4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (57.7 mg, 0.21mmol), Na₂CO₃ (22 mg, 0.21 mmol), and Pd(PPh₃)₂Cl₂ (7.3 mg, 0.01 mmol),followed by DME (1 mL)/EtOH 0.25 mL)/(H₂O (0.25 mL). The vial was purgedwith N₂ for 10 minutes and the reaction mixture was heated at 150° C. ina microwave reactor for 20 minutes. The reaction mixture was filteredthrough celite and the filter cake was washed with EtOAc. The filtratewas concentrated in vacuo to give the crude product which was purifiedby silica gel chromotography (5%-15% MeOH/DCM) to afford6-(2-methoxy-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(50 mg). MS: 551.6 [M+H⁺]).

Step 3:2-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenol

Following GENERAL METHOD 3-1 for methoxy deprotection using thiophenol,6-(2-methoxy-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(50 mg, 0.09 mmol) was treated with thiophenol (0.01 mL, 0.11 mmol) andK₂CO₃ (12 mg, 0.09 mmol) in NMP (2 mL) for 30 minutes at 190° C. toafford2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenoland an impurity (50 mg, MS: 537.6 [M+H⁺]).

Step 4:5-(1H-Imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

To a microwave vial containing2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenol(mixture from previous step, 50 mg, 0.09 mmol) in EtOH (1.0 mL)/DCM (1.0mL) and conc. HCl (8.5 μL) was added BBr₃ (0.46 mL, 0.46 mmol). The vialwas purged with N₂ (2×) and the reaction mixture was heated at 110° C.in a microwave reactor for 30 min. The reaction mixture was filteredthrough celite (pre-packed filter funnel) with a MeOH wash. The filtratewas acidified to pH 3 using 1N HCl and purified by catch and releaseusing SiliaBond Propylsulfonic Acid® (1 g, MeOH as eluent and a 2 Nammonia solution in MeOH to release the material). After evaporation,the material was purified via reverse phase HPLC to afford5-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(2 mg). MS: 407.4 [M+H⁺]. LCMS Rt=0.40 min [Method Q]; ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 8.01 (d, J=9.60 Hz, 1H), 7.57-7.74 (m, 2H), 7.39 (s,1H), 7.14-7.30 (m, 3H), 4.98 (br. s., 1H), 2.92 (s, 3H), 1.62 (d,J=13.14 Hz, 2H), 1.52 (t, J=12.38 Hz, 2H), 1.32 (s, 6H), 1.16 (s, 6H).

Example 42-3 Synthesis of5-(imidazo[1,2-a]pyrazin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Step 1:6-(4-(Imidazo[1,2-a]pyrazin-3-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

To a microwave vial was added6-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Intermediate 9-3, 50 mg, 0.1 mmol),3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (49.6 mg, 0.21 mmol),Na₂CO₃ (44 mg, 0.42 mmol), and Pd(PPh₃)₂Cl₂ (7 mg, 0.01 mmol), followedby DME (1 mL)/EtOH 0.25 mL)/(H₂O (0.25 mL). The vial was purged with N₂for 10 minutes and the reaction mixture was heated at 150° C. in amicrowave reactor for 20 min. The reaction mixture was filtered throughcelite and the filter cake was washed with EtOAc. The filtrate wasconcentrated in vacuo to give the crude product which was purified bysilica gel chromotography (5%-15% MeOH/DCM) to afford6-(4-(imidazo[1,2-a]pyrazin-3-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(49 mg). MS: 476.5 [M+H⁺]).

Step 2:5-(Imidazo[1,2-a]pyrazin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol

Following GENERAL METHOD 3-1 for methoxy deprotection using thiophenol,6-(4-(imidazo[1,2-a]pyrazin-3-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(49 mg, 0.1 mmol) was treated with thiophenol (0.01 mL, 0.12 mmol) andK₂CO₃ (14 mg, 0.11 mmol) in NMP (2 mL) for 30 minutes at 190° C. toafford5-(imidazo[1,2-a]pyrazin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol(8 mg). MS: 458.4 [M+H⁺]; LCMS Rt=0.47 min [Method Q]; ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.16 (s, 1H), 8.41 (d, J=5.05 Hz, 1H), 7.92-7.97 (m,2H), 7.88 (d, J=10.11 Hz, 1H), 7.75 (d, J=8.08 Hz, 1H), 7.31 (s, 1H),7.13 (s, 1H), 7.05 (d, J=9.60 Hz, 1H), 4.99 (br. s., 1H), 3.05 (s, 3H),1.72 (d, J=12.13 Hz, 2H), 1.46 (t, J=12.38 Hz, 2H), 1.39 (s, 6H), 1.23(s, 6H).

Example 42-4 Synthesis of2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenol

To a solution of6-(4-(imidazo[1,2-a]pyrazin-3-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine(Example 42-3, 50 mg, 0.1 mmol) in DCM (2 mL) was added 1 M solution ofBBr₃ in DCM (0.52 mL) dropwise at 78° C. The crude reaction mixture waswarmed to RT and stirred overnight. The reaction was quenched withNaHCO₃ aq solution at 0° C. and extracted with DCM. The organic layerwas dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was acidified to pH 3 using 1N HCl andpurified by catch and release using SiliaBond Propylsulfonic Acid® (1 g,MeOH as eluent and a 2 N ammonia solution in MeOH to release thematerial). After evaporation, the material was purified via reversephase HPLC to afford2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenol(4 mg). MS: 462.4 [M+H⁺]; LCMS Rt=0.36 min [Method Q]; ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 8.03 (d, J=10.11 Hz, 1H), 7.74 (d, J=9.09 Hz, 1H),7.22 (d, J=10.11 Hz, 1H), 6.96 (s, 2H), 6.99 (s, 1H), 5.02 (br. s., 1H),3.88-4.09 (m, 4H), 3.11 (t, J=5.31 Hz, 2H), 2.92 (s, 3H), 1.62 (d,J=12.63 Hz, 2H), 1.51 (t, J=12.38 Hz, 2H), 1.31 (s, 6H), 1.16 (s, 6H).

The following compounds were prepared using similar procedures as inExamples 42-1 to 42-4, and general methods as outlined in the GENERALMETHODS section.

LCMS Example Compound Method Q ¹H NMR 400 MHz 42-5 

M + 1 = 421.4 Rt = 0.39 min (METHANOL-d₄) δ 8.01 (d, J = 10.10 Hz, 1H),7.71 (d, J = 8.08 Hz, 1H), 7.28-7.38 (m, 2H), 7.20 (d, J = 10.11 Hz,1H), 6.73 (s, 1H), 5.00 (br. s., 1H), 2.91 (s, 3H), 2.19 (s, 3H), 1.60(d, J = 3.54 Hz, 2H), 1.53 (d, J = 12.63 Hz, 2H), 1.31 (s, 6H), 1.16 (s,6H) 42-6 

M + 1 = 421.4 Rt = 0.39 min (CHLOROFORM-d) δ ppm 7.77 (d, J = 10.11 Hz,1H), 7.53 (d, J = 8.08 Hz, 1H), 7.32-7.45 (m, 2H), 7.11-7.23 (m, 2H),6.91 (d, J = 10.11 Hz, 1H), 4.98 (br. s., 1H), 3.66 (s, 3H), 2.93 (s,3H), 1.64 (dd, J = 12.38, 3.28 Hz, 2H), 1.48- 1.53 (m, 2H), 1.36 (br.s., 6H), 1.20 (br. s., 6H) 42-7 

M + 1 = 421.4 Rt = 0.37 min (CHLOROFORM-d) δ 7.77 (d, J = 10.11 Hz, 1H),7.55 (d, J = 8.08 Hz, 2H), 7.03 (d, J = 1.52 Hz, 2H), 6.94 (d, J = 9.60Hz, 1H), 6.89 (dd, J = 8.34, 1.77 Hz, 1H), 4.95 (br. s., 1H), 3.67 (s,3H), 2.95 (s, 3H), 1.64 (dd, J = 12.63, 3.54 Hz, 2H), 1.42- 1.52 (m,2H), 1.34 (s, 6H), 1.17 (s, 6H) 42-8 

M + 1 = 452.4 Rt = 0.47 min (METHANOL-d₄) δ 8.03 (d, J = 10.10 Hz, 1H),7.97 (s, 1H), 7.73 (d, J = 8.59 Hz, 1H), 7.50 (br. s., 2H), 7.21 (d, J =9.60 Hz, 1H), 5.11 (br. s., 1H), 2.92 (s, 3H), 1.69 (d, J = 4.04 Hz,2H), 1.57-1.66 (m, 2H), 1.40 (s, 6H), 1.24 (s, 6H) 42-9 

M + 1 = 421.4 Rt = 0.39 min (METHANOL-d₄) δ 7.95 (d, J = 10.11 Hz, 1H),7.61 (d, J = 8.59 Hz, 1H), 7.20 (s, 1H), 7.10-7.18 (m, 3H), 4.93 (br.s., 1H), 2.88 (s, 3H), 2.31 (s, 3H), 1.53-1.62 (m, 2H), 1.39-1.50 (m,2H), 1.28 (s, 6H), 1.12 (s, 6H) 42-10

M + 1 = 435.4 Rt = 0.38 min (METHANOL-d₄) δ 7.98 (d, J = 9.60 Hz, 1H),7.63 (d, J = 8.59 Hz, 1H), 7.28 (s, 1H), 7.14-7.22 (m, 3H), 4.95 (br.s., 1H), 3.56 (s, 3H), 2.90 (s, 3H), 2.31 (s, 3H), 1.60 (d, J = 12.63Hz, 2H), 1.48 (t, J = 12.38 Hz, 2H), 1.29 (s, 6H), 1.14 (s, 6H) 42-11

M + 1 = 450.3 Rt = 0.38 min (METHANOL-d₄) δ ppm 8.63 (s, 1H), 7.99-8.08(m, 2H), 7.81 (d, J = 8.59 Hz, 1H), 7.25-7.31 (m, 2H), 7.23 (d, J =10.11 Hz, 1H), 5.06 (br. s., 1H), 2.93 (s, 3H), 1.65 (d, J = 12.13 Hz,2H), 1.55 (t, J = 12.38 Hz, 2H), 1.34 (s, 6H), 1.19 (s, 6H)

Example 43-1 Synthesis of2-(6-((3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

Step 1: (3aR,6aS)-tert-Butyl5-(6-chloropyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a solution of 3,6-dichloropyridazine (462 mg, 3.10 mmol) in n-butanol(8 mL) was added DIPEA (1.354 ml, 7.75 mmol) and (3aR,6aS)-tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (658 mg, 3.1 mmol). Thereaction mixture was heated at 120° C. for 2 hour, and then diluted withDCM and water. The organic layer was separated and concentrated to abrownish oil, which was purified by silica gel chromatography (0-25%EtOAc/DCM) to afford (3aR,6aS)-tert-butyl5-(6-chloropyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(730 mg, 2.180 mmol, 70% yield), MS (M+1)=325.2.

Step 2: (3aR,6aS)-tert-Butyl5-(6-(4-chloro-2-hydroxyphenyl)pyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

The reaction mixture of (3aR,6aS)-tert-butyl5-(6-chloropyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(325 mg, 1 mmol),5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (280 mg,1.100 mmol), sodium carbonate (318 mg, 3.00 mmol) and PdCl₂(dppf).CH₂Cl₂(61.2 mg, 0.075 mmol) in dioxane (5 mL) and water (5.00 mL) was degassedby bubbling N₂ for 10 minutes. After heating at 90° C. overnight, thereaction mixture was filtered through celite and washed with EtOAc. Thefiltrate was concentrated and the residue was purified by silica gelchromatography (0-10% MeOH/DCM) to afford (3aR,6aS)-tert-butyl5-(6-(4-chloro-2-hydroxyphenyl)pyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(180 mg, 0.432 mmol, 43.2% yield) MS (M+1)=417.0.

Step 3: (3aR,6aS)-tert-Butyl5-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a 10 mL microwave vial, was added (3aR,6aS)-tert-butyl5-(6-(4-chloro-2-hydroxyphenyl)pyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(0.182 g, 0.437 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.385 g, 1.310 mmol),chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)(0.035 g, 0.044 mmol) and Cs₂CO₃ (0.427 g, 1.310 mmol), followed byadding 1,4-dioxane (2 mL) and water (0.5 mL). The reaction mixture wasevacuated and filled with N₂ twice then heated at 90° C. overnight. Thereaction mixture was filtered through celite and washed with DMSO andMeOH. The filtrate was acidified with 1N HCl and stirred at RT for 3hour, then extracted with DCM. The aqueous layer was basified with 2MNH₂ in MeOH and a brownish precipitate formed, which was filtered andwashed with DMSO to afford a grey solid2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol(82 mg, 0.224 mmol, 51.2% yield). MS (M+1)=349.1. The DMSO wash solutionwas concentrated to afford a DMSO solution of desired(3aR,6aS)-tert-butyl5-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(75 mg, 0.167 mmol, 38% yield), MS (M+1)=449.1, which was used directlyin the next step.

Step 4: 2-(6-((3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin3-yl)-5-(1H-pyrazol-4-yl)phenol

To a solution of (3aR,6aS)-tert-butyl5-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(75 mg, 0.167 mmol) in 1 mL of dioxane was added 4N HCl in dioxane (1mL, 4.00 mmol). The reaction mixture was stirred at RT overnight, andthen basified with 2N NH₃ in MeOH to form a precipitate which wasseparated via centrifugation to provide a dark solid,2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin3-yl)-5-(1H-pyrazol-4-yl)phenol (50 mg, 0.136 mmol, 82% yield) MS(M+1)=349.1.

Step 5:2-(6-((3aR,6aS)-5-(2-((tert-Butyldimethylsilyl)oxy)ethyl))hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

To a solution of2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol(31.4 mg, 0.09 mmol), 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (47.1mg, 0.270 mmol), and sodium triacetoxyhydroborate (57.2 mg, 0.270 mmol)in CH₂Cl₂ (2 mL), was added acetic acid (0.013 mL, 0.225 mmol). Thereaction mixture was stirred at RT overnight, then quenched with waterand diluted with DCM. The organic layer was acidified with 1N HClsolution to pH˜3 and filtered to remove insoluble materials. Thefiltrate was loaded onto an SCX column, washed with MeOH, then elutedwith 7N NH₃ in MeOH. Concentration provided a brownish solid, 2-(6-((3aR,6aS)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol(23 mg, 0.020 mmol, 51% yield), MS (M+1)=507.1.

Step 6:2-(6-((3aR,6aS)-5-(2-Hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol

To a solution of2-(6-((3aR,6aS)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol(20 mg, 0.039 mmol) in dioxane (2 mL) was added 4N HCl in dioxane (1 mL,4.00 mmol). The reaction mixture was stirred at RT overnight, thenbasified with 2N NH₃ in MeOH and concentrated. The crude product waspurified via preparative HPLC to give an off-white solid2-(6-((3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol(6.5 mg, 0.016 mmol, 41% yield). LCMS Rt=0.87 min [Method Q]; MS(M+1)=393.1. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.01 (d, J=9.60 Hz,1H), 7.93 (s, 2H), 7.69 (d, J=8.08 Hz, 1H), 7.08-7.19 (m, 3H), 3.67-3.77(m, 4H), 3.56 (d, J=11.12 Hz, 2H), 3.11 (br. s., 2H), 2.97-3.05 (m, 2H),2.72 (t, J=5.81 Hz, 2H), 2.63-2.70 (m, 2H).

The following compounds were prepared using similar procedures as inExample 43-1, and general methods as outlined in the GENERAL METHODSsection.

LCMS Example Structure ¹H NMR, 400 MHz Method Q 43-2

(DMSO-d₆) δ 8.22 (d, J = 2.5 Hz, 2H), 7.94-8.00 (m, 1H), 7.83 (d, J =8.1 Hz, 1H), 7.15-7.23 (m, 3H), 3.71-3.86 (m, 2H), 3.45- 3.53 (m, 2H),3.31-3.39 (m, 2H), 3.16-3.23 (m, 1H), 3.00-3.11 (m, 2H), 2.86-2.93 (m,1H) Rt = 0.38 min M + 1 = 349.1 43-3

(METHANOL-d₄) δ 8.01 (d, J = 10.1 Hz, 1H), 7.93 (s, 2H), 7.68 (d, J =8.1 Hz, 1H), 7.08- 7.17 (m, 3H), 3.72 (dd, J = 10.9, 7.8 Hz, 2H), 3.56(dd, J = 10.9, 2.3 Hz, 2H), 3.09-3.20 (m, 2H), 2.90-2.99 (m, 2H), 2.67(dd, J = 9.9, 2.8 Hz, 2H), 2.45 (s, 3H) Rt = 0.38 min M + 1 = 363.2 43-4

(METHANOL-d₄) δ 7.88 (d, J = 9.6 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.38(d, J = 7.1 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.10 (dd, J = 8.3, 1.8Hz, 1H), 6.97 (d, J = 9.6 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 6.51 (dd, J= 7.1, 2.0 Hz, 1H), 3.66 (d, J = 6.6 Hz, 2H), 3.56-3.63 (m, 2H), 3.52(s, 3H), 3.20-3.40 (br. s., 2H), 3.05-3.35 (br. s., 2H), 2.73 (br. s.,2H), 2.50 (br. s., 3H) Rt = 0.41 min M + 1 = 404.3 43-5

(METHANOL-d₄) δ 8.03 (d, J = 10.1 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H),7.55 (d, J = 7.1 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H), 7.19 (dd, J = 8.3,1.8 Hz, 1H), 7.13 (d, J = 9.6 Hz, 1H), 6.82 (d, J = 1.5 Hz, 1H), 6.64(dd, J = 7.1, 2.0 Hz, 1H), 4.01 (d, J = 12.1 Hz, 1H), 3.74-3.83 (m, 1H),3.54-3.69 (m, 2H), 3.60 (s, 3H), 3.49 (br. s., 1H), 3.37 (br. s., 1H),3.20 (br. s., 1H), 2.72 (d, J = 7.6 Hz, 1H), 2.62 (s, 3H), 2.36 (d, J =9.6 Hz, 1H), 1.89 (d, J = 8.6 Hz, 1H) Rt = 0.41 min M + 1 = 404.2 43-6

(METHANOL-d₄) δ 7.83 (d, J = 10.1 Hz, 1H), 7.78-7.81 (m, 2H), 7.55 (d, J= 8.1 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 8.1, 1.5 Hz, 1H),6.90 (d, J = 9.6 Hz, 1H), 3.51-3.62 (m, 2H), 3.47 (d, J = 10.6 Hz, 1H),3.30 (s, 1H), 2.74-2.84 (m, 1H), 2.61-2.74 (m, 3H), 1.89-2.00 (m, 1H),1.78-1.89 (m, 1H), 1.59- 1.70 (m, 2H), 1.46-1.59 (m, 2H) Rt = 0.42 minM + 1 = 377.2 43-7

(METHANOL-d₄) δ 7.97 (d, J = 10.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H),7.53 (d, J = 7.1 Hz, 1H), 7.16 (d, J = 1.5 Hz, 1H), 7.13 (dd, J = 8.3,1.8 Hz, 1H), 7.02 (d, J = 9.6 Hz, 1H), 6.75 (d, J = 1.5 Hz, 1H), 6.60(dd, J = 7.1, 2.0 Hz, 1H), 3.56-3.65 (m, 2H), 3.53 (s, 3H), 3.45-3.50(m, 1H), 3.30 (d, J = 10.6 Hz, 1H), 2.75-2.84 (m, 1H), 2.62-2.75 (m,3H), 1.91- 2.03 (m, 1H), 1.79-1.90 (m, 1H), 1.60-1.71 (m, 2H), 1.49-1.60(m, 2H) Rt = 0.44 min M + 1 = 418.2

Example 44 Synthesis of Example 17-135-(1H-Pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolhydrochloride Step 1a: Preparation of3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine

To a 30-L reactor was charged 3,6-dichloropyridazine (1 kg, 6.7 mol),2,2,6,6-tetramethylpiperidin-4-ol (1.05 kg, 6.7 mol) and THF (5 L). Themixture was stirred and cooled to −5° C. tBuOK (1.13 kg, 10.1 mol)dissolved in THF (10 L) was added slowly to the reactor while keepingthe temperature at −5-0° C. The reaction mixture became deep brownduring addition. After the addition was complete, the mixture wasstirred for 1 hour at −5-0° C., after which time HPLC analysis showedthat the reaction was complete. Ice water (1:1, 10 kg) was added slowlyto quench the reaction. The mixture was concentrated under reducedpressure to remove most of the THF. The residue was extracted with EtOActwice (10 L+5 L). The combined organic layer was washed with water (10L×3), then concentrated under reduced pressure to give a black residue.Petroleum ether (25 L) was added to this residue while stirring. Thedark solid that formed was removed by filtration. The pale yellowfiltrate was concentrated under reduced pressure to give a yellow solid,which was dried at 50° C. in vacuo to give3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (1.3 kg,4.8 mol), and was used in the next step without further purification. MSm/z 270.1 [M+H]; ¹H-NMR: (CDCl₃, 400 MHz) δ 7.36 (d, J=9.2 Hz, 1H), 6.90(d, J=9.2 Hz, 1H), 5.74 (m, 1H), 2.20 (dd, J_(a)=4 Hz, J_(b)=12.4 Hz,2H), 1.30 (m, 14H).

Step 1b: Preparation of5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

To a 30-L reactor was charged 2-bromo-5-chlorophenol (2.0 kg, 9.65 mol),B₂Pin₂ (2.7 kg, 10.6 mol), AcOK (1.9 kg, 19.3 mol) and 1,4-dioxane (15L). The mixture was stirred and purged with nitrogen 3 times.PdCl₂(dppf)-CH₂Cl₂ (100 g, 0.12 mol) was added under nitrogen and themixture was heated to 75° C. (the oil bath could be removed in case ofstrong exotherm). The mixture was heated at 90° C. for 16 hours, afterwhich time HPLC analysis showed that the reaction was complete. Aftercooling to 35° C., the mixture was filtered through a pad of Celite. Thefiltrate 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol(1.22 kg, 4.8 mol) solution was used in next step without furtherpurification. MS m/z 253.1 [M−H]; ¹H-NMR: (CDCl₃, 400 MHz) δ 9.2 (br,1H), 7.25 (d, J=8 Hz, 1H), 6.64 (d, J=1.6 Hz, 1H), 6.62 (dd, J_(b)=8 Hz,J_(b)=1.6 Hz, 1H), 1.05 (s, 12H).

Step 2: Preparation of5-chloro-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolhydrochloride

To the solution containing5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.22 kg,4.8 mol) from the previous step was added3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (1.17 kg,4.4 mol). K₃PO₄-3H₂O (2.34 kg, 8.8 mol) was dissolved in water (5 L)then added to the above solution. The mixture was purged with nitrogen 3times. Pd(PPh₃)₄ (500 g, 0.42 mol) was added under nitrogen, and thereaction mixture was heated to reflux at 89° C. for 16 hours. After 16hours, HPLC showed that the reaction was complete. After cooling to roomtemperature, the mixture was filtered through a pad of celite and thefiltrate was concentrated under reduced pressure. CH₂Cl₂ (10 L×3) and10% K₂CO₃ solution (15 L) were added to the above residue. The organiclayers were separated and combined, followed by washing with water twice(10 L×2) and concentration under reduced pressure to give yellow oil.MTBE (10 L) was used to dissolve the yellow oil. Petroleum ether (4 L)was added slowly with stirring. A few dark solids precipitated and wereremoved by filtration. The filtrate was concentrated under reducedpressure and dissolved in CH₂Cl₂ (20 L). 2N HCl (5 L) was added slowlyand a large amount of precipitate formed. After stirring for another 1hour, the solid was collected by filtration and washed with EtOAc (2 L).The solid was dried in vacuo at 50° C. to give5-chloro-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolhydrochloride (0.9 kg, 2.2 mol). MS m/z 362.0 [M+H]⁺; ¹H-NMR: (DMSO-d⁶,400 MHz) δ 9.26 (d, J=11.6 Hz, 1H), 8.49 (d, J=12 Hz, 1H), 8.38 (d,J=9.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.44 (d, J=9.6 Hz, 1H), 7.07 (d,J=2 Hz, 1H), 7.02 (dd, J_(a)=2 Hz, J_(b)=8.4 Hz, 1H), 5.73 (m, 1H), 2.31(dd, J_(a)=4 Hz, J_(b)=13.2 Hz, 2H), 1.84 (dd, J_(a)=11.6 Hz, J_(b)=2Hz, 2H), 1.51 (s, 6H), 1.49 (s, 6H).

Step 3: Preparation of5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol

A 1-L flask was charged with5-chloro-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolhydrochloride (9.2 g, 23 mmol), N-Boc-Pyrazole-4-boronic acid pinacolester (10.2 g, 35 mmol), Cs₂CO₃ (15 g, 46 mmol), 1,4-dioxane (100 mL)and water (25 mL). The mixture was purged with nitrogen 3 times. X-Phos(0.88 g, 1.85 mmol) and Pd₂ dba₃ (0.845 g, 0.922 mmol) were added. Themixture was purged with nitrogen 3 times, then heated at 80° C. for 3hrs. By HPLC analysis, the reaction was complete. 37% HCl (10 mL) wasadded slowly over 20 min. Ethanol (100 mL) and H₂O (200 mL) were addedand the reaction mixture was heated to 75-80° C. for 16 hours. Thereaction mixture was cooled to 50-60° C., and the insoluble black solidswere filtered. The filtrate was cooled to 30° C., and 2N NaOH (50 mL)was added to basify the solution to pH 8-9. The resulting precipitatewas stirred for 30 min, then filtered and dried under vacuum at 50° C.to give5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolas yellow solid. HRMS m/z 394.2239 [M+H]; ¹H-NMR: (DMSO-d⁶, 400 MHz) δ13.2 (br, 1H), 13.0 (br, 1H), 8.44 (d, J=8 Hz, 1H), 8.14 (br, 2H), 7.93(d, J=8 Hz, 1H), 7.39 (d, J=12 Hz, 1H), 7.24 (d, J=8 Hz, 2H), 5.64 (m,1H), 2.10 (dd, J_(a)=4 Hz, J_(b)=12 Hz, 2H), 1.26-1.30 (m, J=8 Hz, 2H),1.23 (s, 6H), 1.10 (s, 6H). ¹³C-NMR: (DMSO-d⁶, 100 MHz) δ 162.80,158.55, 155.97, 136.13, 128.30, 127.71, 120.42, 120.01, 116.26, 115.13,113.44, 71.32, 50.99, 43.20, 34.33, 29.14.

Step 4: Preparation of5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolhydrochloride

To a 2-L flask was added5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol(50 g, 127 mmol), 37% HCl (21 mL, 254 mmol), H₂O (1 L) and EtOH (1 L).SMOPEX-234 (10 g, Pd scavenger) and activated charcoal (10 g) were alsoadded. The mixture was heated at reflux (78° C.) for 3 hours. Theresulting black mixture was allowed to cool to 60° C., and the Pdscavenging agents were filtered off at 50-60° C. The filtrate was cooledto 15° C. gradually over 1 h, and a pale yellow precipitate formed.After 2 h, the solid was collected by filtration, washed with EtOH (50mL), and dried under vacuum at 50° C. to give5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenolhydrochloride (27.2 g, 63 mmol). HRMS m/z 394.2222 [M+H]; ¹H-NMR:(DMSO-d⁶, 400 MHz) δ 13.09 (br, 2H), 9.41 (d, J=12 Hz, 1H), 8.61 (d,J=12 Hz, 1H), 8.49 (d, J=Hz, 1H), 8.15 (br, 2H), 7.95 (d, J=8 Hz, 1H),7.46 (d, J=8 Hz, 1H), 7.26 (d, J=8 Hz, 2H), 5.72 (m, 1H), 2.33 (dd,J_(a)=3.2 Hz, J_(b)=13.2 Hz, 2H), 1.86-1.92 (m, J_(a)=8 Hz, 2H), 1.23(s, 6H), 1.10 (s, 6H); ¹³C-NMR: (DMSO-d⁶, 100 MHz) δ 162.34, 158.51,156.41, 136.29, 128.72, 127.94, 120.40, 119.95, 116.37, 115.18, 113.45,67.94, 56.69, 29.23, 25.10; XRPD: 13.47505, 14.29462, 14.99017,16.55045, 17.60726, 19.69314, 21.89296, 23.89703, 25.82989, 27.13969,28.47844, 36.94252, 43.77528.

LCMS Conditions:

Condition A:

Column: Acquity BEH 1.7 mm 2.1×50 mm at 50° C.

Neutral system; Gradient: 2 to 98% B in 4.4 min−flow 1 mL/min; Eluent A:Water+3.75 mM ammonium acetate+2% ACN; Eluent B: Acetonitrile+7.5 mMammonium acetate;

Condition B:

Column: INERTSIL C8-3, 3 μm×33 mm×3.0 mm at 40° C.

Flow rate: 2 mL/min

Mobile phase: A) 5 mM aqueous HCOONH₄, B) MeOH/CH₃CN (1/1, v/v)

Gradient: linear gradient from 5% A to 95% B in 2 min

Condition Q:

Waters Acquity UPLC system

Waters Acquity UPLC BEH C18 1.7 um, 2.1×30 mm (Part#: 186002349)

Flow rate: 1 mL/min

Temperature: 55 C (column temp)

Mobile Phase Compositions:

A. 0.05% formic acid in water.

B. 0.04% formic acid in methanol

Gradient:

Time (min) Flow (mL/min) % A % B 0 1.000 95.0 5.0 0.10 1.000 95.0 5.00.50 1.000 20.0 80.0 0.60 1.000 5.0 95.0 0.80 1.000 5.0 95.0 0.90 1.00095.0 5.0 1.15 1.000 95.0 5.0

Abbreviations:

Ac: Acetyl aq: aqueous ACN: acetonitrile B₂pin: Bis(pinacolato)diboronBOC, Boc: tertiary butyl carboxy BOC₂O: tertiary butylcarboxyanhydrideBn: benzyl bs: broad singlet BSA: Bovine Serum Albumin 9-BBN:9-Borabicyclo[3.3.1]nonane CH₃CN: acetonitrile CHN: C, H, N elementalanalysis d: doublet dd: doublet of doublets DCM: dichloromethane DIEA:diethylisopropylamine DMA: dimethylacetamide DIBAL: diisobutylaluminiumhydride DAST: Diethylaminosulfur trifluoride DIPEA:N,N-diisopropylethylamine DME: 1,2-dimethoxyethane DMF:N,N-dimethylformamide DMSO: dimethylsulfoxide DIAD: Diisopropylazodicarboxylate DCC: N,N′-Dicyclohexylcarbodiimide Dtbpy:4,4′-di-tert-butyl bipyridine dppf: 1,1′-bis(diphenylphosphino)ferroceneEC₅₀: half maximal effective concentration ELISA: enzyme-linkedimmunosorbent assay Et and EtOAc: ethyl and ethyl acetate Et₂O: ether,diethyl ether EtOH: ethanol g: gram HATU:O-(7-azobenzotriazol-1-yl)-1,1,3,3- HPLC: High Pressure Liquidtetramethyluroniumhexafluorophosphate Chromatography HRP: horse radishperoxidase HOBt: Hydroxybenzotriazole h, hr: hour(s) LC and LCMS: liquidchromatography and L: liter liquid chromatography and mass spectrometryM: Molar Me: methyl M as in M + 1: Molecular Mass M and mM: Molar andmillimolar m: multiplet mAB: monoclonal antibody MeOD: methanol-d4 MS:mass spectrometry MeOH: methanol MTBE: methyl tert-butyl ether min:minutes m/z: mass to charge ratio mL: milliliter mm: millimeter mg:milligram mmol, m: millimole, mole MHz, Hz: mega Hertz; Hertz N: normalNMP: N-methylpyrrolidone nM: nanomolar NMM: N-methyl morpholine NMR:Nuclear Magnetic Resonance PBST: Phosphate buffered saline withSpectroscopy Tween PdCl₂(dppf)•CH₂Cl₂: 1,1′-Bis(diphenyl- ppm: parts permillion phosphino)ferrocene-palladium(II)dichloride dichloromethanecomplex pM: picomolar PhSH: thiophenol q: quartet RIPA:radio-immunoprecipitation assay Rt: retention time RT: room temperaturesat: saturated s: singlet SFC: Supercritical Fluid Chromatography SCX:Strong Cation Exchange SPhos: 2-Dicyclohexylphosphino-2′,6′- TFA:trifluoroacetic acid dimethoxybiphenyl t: triplet TBAF:tetra-butylammonium fluoride TBSCl: tert-butyldimethylsilyl chloridetBu: tert-butyl TEA: triethylamine Tf: triflate THF: tetrahydrofuranTLC: thin layer chromatography TMB: tertramethylbenzidine TMSOTf:trimethylsilyl trifluoromethanesulfonate uL, mL and L: microliter,milliliter and liter UV: ultraviolet wt: weight XPhos:2-Dicyclohexylphosphino-2′,4′,6′- XPhos Palladacycle: Chloro(2-triisopropylbiphenyl dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2- aminoethyl)phenyl] palladium(II)methyl-t-butylether

Biological Example 1

A cellular SMN ELISA was used to measure the effects of low molecularweight compounds on SMN protein elevation. Cells from a myoblast cellline derived from the SMNdelta7 mouse model (kind gift from SteveBurden, NYU) were seeded into a 384-well plate at a density of 3000cells/well and treated with compounds for 24 hours. ELISA capture plateswere prepared by coating 384-well plates (Immulon 4HBX) with 0.5 ug/mLof anti-SMN mAb (BD Science, Catalog number 610647) at 4° C. overnight.The plates were washed 5 times with 110 uL of PBS-Tween (0.05% Tween-20,PBST), blocked with 100 uL of 1% BSA in PBST for 2 hours and washed (5times) with 100 uL of PBST. After 24 hours of compound treatment cellswere lysed in a modified RIPA-buffer, on ice for 1 hour. 20 uL of lysateand 20 uL of 1% BSA were then added to the ELISA capture plates andincubated at 4° C. overnight. Plates were washed (5 times) with PBST andthen incubated with 1:100 dilution of primary rabbit anti-SMN polyclonalantibody (Santa cruz, Catalog number SC-15320) at room temperature for 1hour and subsequently washed (5 times) with 110 uL of PBST. This wasfollowed by addition of 1:100 Goat anti-Rabbit IgG-HRP linked (CellSignaling, Catalog number 7074) secondary antibody for 1 hour. Plateswere then washed with PBST and incubated with 40 uL TMB substrate (CellSignaling, Catalog number 7004 L) at room temperature for 1-10 minuteswith shaking. The reaction was stopped by addition of 40 uL of stopsolution (Cell signaling, Catalog number 7002 L) and absorption wasmeasured at 450 nm. Data was reported as fold activation over DMSOcontrol, and EC₅₀.

ELISA assay condition 1: compound concentration range 20 nM-10 uM; ELISAassay condition 2: compound concentration 100 pM-10 uM.

Activity TABLE Data generated in Biological Example 1 using ELISAconditions 1 or 2. SMN activity ELISA Example Fold, EC₅₀ condition  1-12.62, 810 nM 2  1-2 2.40, 600 nM 2  1-3 2.45, 726 nM 2  1-4 2.05, 90 nM1  1-5 2.50, 650 nM 1  1-6 2.00, 2.44 uM 1  1-7 2.07, 1.55 uM 1  1-82.18, 320 nM 1  1-9 2.81, 398 nM 2  1-10 2.75, 1.1 uM 2  1-11 2.67, 3.90uM 2  1-12 2.54, 367 nM 2  1-13 2.22, 661 nM 2  1-14 3.13, 252 nM 2 1-15 2.93, 197 nM 2  1-16 2.28, 2.98 uM 2  1-17 2.37, 926 nM 2  1-182.69, 1.13 uM 1  1-19 3.10, 740 nM 1  1-20 3.04, 470 nM 1  1-21 2.49,630 nM 1  1-22 2.71, 867 nM 2  2-1 2.68, 1.37 uM 1  2-2 2.37, 1.03 uM 1 2-3 2.46, 1.20 uM 1  3-1 2.31, 10 nM 2  3-2 2.06, 1.07 uM 1  3-3 2.48,64 nM 1  3-4 2.03, 620 nM 1  3-5 2.38, 100 nM 1  3-6 3.01, 110 nM 2  3-72.67, 4.53 uM 1  3-8 2.72, 1.58 uM 2  3-9 2.88, 323 nM 2  3-10 2.53, 855nM 2  3-11 2.47, 220 nM 2  3-12 2.70, 129 nM 1  4-1 2.53, 148 nM 2  5-12.97, 54 nM 2  6-1 2.04, 630 nM 2  7-1 2.54, 2.73 uM 1  8-1 2.72, 280 nM1  9-1 2.96, 17 nM 1 10-1 2.99, 31 nM 2 11-1 2.79, 23 nM 2 12-1 3.13, 4nM 2 13-1 3.46, 20 nM 2 14-1 2.98, 4 nM 2 15-1 2.90, 14 nM 2 16-1 2.66,77 nM 2 16-2 3.21, 15 nM 2 16-3 2.39, 625 nM 2 16-4 2.71, 94 nM 2 16-52.41, 24 nM 2 17-1 2.58, 339 nM 2 17-2 2.62, 70 nM 1 17-3 2.75, 183 nM 217-4 3.25, 92 nM 2 17-5 2.78, 2.44 uM 2 17-6 2.58, 443 nM 2 17-7 2.50,617 nM 2 17-8 2.18, 3.15 uM 2 17-9 2.63, 1.67 uM 2  17-10 2.03, 945 nM 2 17-11 3.01, 665 nM 2  17-12 3.29, 31 nM 2  17-13 4.00, 17 nM 2 18-13.07, 296 nM 2 18-2 1.97, 3.23 uM 2 18-3 1.95, 660 nM 1 18-4 2.84, 388nM 2 18-5 2.66, 151 nM 2 18-6 2.54, 268 nM 2 18-7 2.67, 2.66 uM 2 18-82.32, 983 nM 2 18-9 1.93, 1.18 uM 1  18-10 2.55, 386 nM 2  18-11 2.53,320 nM 2  18-12 2.62, 792 nM 2  18-13 2.28, 1.24 uM 2  18-14 2.62, 17 nM1  18-15 2.30, 714 nM 2  18-16 3.25, 227 nM 2  18-17 2.85, 158 nM 2 18-18 2.57, 56 nM 2 19-1 2.77, 477 nM 2 19-2 2.73, 402 nM 2 19-3 2.19,155 nM 2 19-4 2.47, 25 nM 2 19-5 2.58, 402 nM 2 19-6 2.33, 40 nM 2 19-73.07, 37 nM 2 20-1 2.75, 18 nM 2 20-2 2.79, 4 nM 2 20-3 3.42, 8 nM 220-4 2.32, 310 nM 1 20-5 2.66, 6 nM 2 20-6 2.18, 50 nM 2 20-7 2.75, 7 nM2 20-8 2.61, 30 nM 2 20-9 2.44, 176 nM 2 21-1 2.35, 959 nM 2 21-2 2.69,206 nM 2 22-1 2.68, 39 nM 2 23-1 2.32, 3.65 uM 2 24-1 3.14, 16 nM 2 24-22.33, 157 nM 2 24-3 2.75, 120 nM 2 24-4 3.06, 16 nM 2 24-5 2.99, 47 nM 224-6 2.39, 6 nM 2 24-7 2.57, 31 nM 2 24-8 2.39, 7 nM 2 24-9 2.65, 338 nM2  24-10 3.14, 113 nM 2  24-11 2.54, 133 nM 2  24-12 2.80, 70 nM 2 25-12.58, 84 nM 2 25-2 3.44, 8 nM 2 25-3 2.39, 119 nM 2 25-4 2.30, 199 nM 225-5 2.36, 96 nM 2 25-6 2.16, 107 nM 2 26-1 3.18, 14 nM 2 26-2 2.61, 97nM 2 26-3 2.70, 47 nM 2 26-4 2.22, 649 nM 2 26-5 2.14, 313 nM 2 27-12.35, 305 nM 2 27-2 2.83, 165 nM 2 27-3 2.75, 619 nM 2 28-1 3.41, 475 nM2 29-1 2.49, 113 nM 2 30-1 2.99, 8 nM 2 30-2 2.98, 62 nM 2 31-1 3.03,200 nM 2 32-1 2.67, 125 nM 2 32-2 2.49, 396 nM 2 32-3 2.44, 201 nM 232-4 2.09, 168 nM 2 32-5 2.52, 231 nM 2 32-6 2.69, 92 nM 2 32-7 3.27,551 nM 2 32-8 2.61, 433 nM 2 32-9 2.90, 485 nM 2 33-1 2.29, 349 nM 234-1 2.80, 7 nM 2 34-2 2.49, 2 nM 2 34-3 2.56, 27 nM 2 34-4 2.34, 37 nM2 34-5 2.75, 56 nM 2 35-1 2.79, 27 nM 2 35-2 2.84, 10 nM 2 35-3 2.62, 11nM 2 35-4 2.11, 131 nM 2 35-5 2.44, 6 nM 2 35-6 2.21, 51 nM 2 36-1 2.04,652 nM 2 37-1 2.59, 118 nM 2 38-1 3.17, 60 nM 2 39-1 2.65, 1026 nM 239-2 3.04, 408 nM 2 40-1 2.58, 79 nM 2 40-2 2.78, 25 nM 2 40-3 3.03, 11nM 2 40-4 2.14, 15 nM 2 40-5 3.59, 17 nM 2 40-6 2.16, 208 nM 2 40-72.80, 4 nM 2 40-8 3.18, 16 nM 2 41-1 2.78, 125 nM 2 41-2 2.68, 50 nM 241-3 3.10, 66 nM 2 41-4 3.29, 80 nM 2 41-5 2.88, 175 nM 2 41-6 2.67, 10nM 2 41-7 2.87, 7 nM 2 41-8 3.18, 62 nM 2 41-9 4.2, 72 nM 2  41-10 2.80,59 nM 2  41-11 2.78, 12 nM 2  41-12 2.92, 103 nM 2  41-13 3.50, 308 nM 2 41-14 3.21, 84 nM 2  41-15 2.56, 145 nM 2  41-16 2.30, 62 nM 2  41-172.88, 170 nM 2  41-18 2.44, 17 nM 2  41-19 2.62, 17 nM 2  41-20 2.63, 32nM 2 42-1 2.28, 117 nM 2 42-2 2.06, 26 nM 2 42-3 2.92, 99 nM 2 42-42.41, 853 nM 2 42-5 3.22, 202 nM 2 42-6 2.49, 66 nM 2 42-7 2.51, 55 nM 242-8 2.82, 756 nM 2 42-9 2.85, 15 nM 2  42-10 3.10, 57 nM 2  42-11 3.37,239 nM 2 43-1 3.04, 40 nM 2 43-2 2.54, 58 nM 2 43-3 2.39, 19 nM 2 43-42.94, 41 nM 2 43-5 2.29, 159 nM 2 43-6 2.32, 156 nM 2 43-7 2.42, 156 nM2

What is claimed is:
 1. A compound or salt thereof according to Formula (I)

A is 2-hydroxy-phenyl which is substituted with 0, 1, 2, or 3 substituents independently selected from C₁-C₄alkyl, wherein 2 C₁-C₄alkyl groups can combine with the atoms to which they are bound to form a 5-6 membered ring and is substituted with 0 or 1 substituents selected from oxo, oxime and hydroxy,haloC₁-C₄alkyl, dihaloC₁-C₄alkyl, trihaloC₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄alkoxy-C₃-C₇cycloalkyl, haloC₁-C₄alkoxy, dihaloC₁-C₄alkoxy, trihaloC₁-C₄alkoxy, hydroxy, cyano, halogen, amino, mono- and di-C₁-C₄alkylamino, heteroaryl, C₁-C₄alkyl substituted with hydroxy, C₁-C₄alkoxy substituted with aryl, amino, —C(O)NH C₁-C₄alkyl-heteroaryl, —NHC(O)—C₁-C₄alkyl-heteroaryl, C₁-C₄alkyl C(O)NH— heteroaryl, C₁-C₄alkyl NHC(O)— heteroaryl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl or 5, 6 or 9 membered heterocycle containing 1 or 2 heteroatoms, independently, selected from S, O and N, wherein heteroaryl has 5, 6 or 9 ring atoms, 1, 2 or 3 ring heteroatoms selected from N, O and S and substituted with 0, 1, or 2 substituents independently selected from oxo, hydroxy, nitro, halogen, C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkoxy, C₃-C₇cycloalkyl, C₁-C₄alkyl-OH, trihaloC₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, —C(O)NH₂, —NH₂, —NO₂, hydroxyC1-C₄alkylamino, hydroxyC₁-C₄alkyl, 4-7member heterocycleC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- and di-C₁-C₄alkylaminoC₁-C₄alkyl; or A is 2-naphthyl optionally substituted at the 3 position with hydroxy and additionally substituted with 0, 1, or 2 substituents selected from hydroxy, cyano, halogen, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₅alkoxy, wherein the alkoxy is unsubstituted or substituted with hydroxy, C₁-C₄alkoxy, amino, N(H)C(O)C₁-C₄alkyl, N(H)C(O)₂ C₁-C₄alkyl, alkylene 4 to 7 member heterocycle, 4 to 7 member heterocycle and mono- and di-C₁-C₄alkylamino; or A is 6 member heteroaryl having 1-3 ring nitrogen atoms, which 6 member heteroaryl is substituted by phenyl or a heteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatoms independently selected from N, O and S and substituted with 0, 1, or 2 substituents independently selected from C₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- and di-C₁-C₄alkylaminoC₁-C₄alkyl; or A is bicyclic heteroaryl having 9 to 10 ring atoms and 1, 2, or 3 ring heteroatoms independently selected from N, O or S, which bicyclic heteroaryl is substituted with 0, 1, or 2 substituents independently selected from cyano, halogen, hydroxy, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy and C₁-C₄alkoxy substituted with hydroxy, C₁-C₄alkoxy, amino and mono- and di-C₁-C₄alkylamino; or A is tricyclic heteroaryl having 12 or 13 ring atoms and 1, 2, or 3 ring heteroatoms independently selected from N, O or S, which tricyclic heteroaryl is substituted with 0, 1, or 2 substituents independently selected from cyano, halogen, hydroxy, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄alkoxy substituted with hydroxy, C₁-C₄alkoxy, amino, mono- and di-C₁-C₄alkylamino and heteroaryl, wherein said heteroaryl has 5, 6 or 9 ring atoms, 1, 2 or 3 ring heteroatoms selected from N, O and S and substituted with 0, 1, or 2 substituents independently selected from oxo, hydroxy, nitro, halogen, C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkoxy, C₃-C₇cycloalkyl, C₁-C₄alkyl-OH, trihaloC₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, —C(O)NH₂, —NH₂, —NO₂, hydroxyC1-C₄alkylamino, hydroxyC₁-C₄alkyl, 4-7member heterocycleC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- and di-C₁-C₄alkylaminoC₁-C₄alkyl; B is a group of the formula:

Wherein m, n and p are independently selected from 0 or 1; R, R₁, R₂, R₃, and R₄ are independently selected from the group consisting of hydrogen, C₁-C₄alkyl, which alkyl is optionally substituted with hydroxy, amino or mono- and di-C₁-C₄alkylamino; R₅ and R₆ are independently selected from hydrogen and fluorine; or R and R₃, taken in combination form a fused 5 or 6 member heterocyclic ring having 0 or 1 additional ring heteroatoms selected from N, O or S; R₁ and R₃, taken in combination form a C₁-C₃alkylene group; R₁ and R₅, taken in combination form a C₁-C₃alkylene group; R₃ and R₄, taken in combination with the carbon atom to which they attach, form a spirocyclicC₃-C₆cycloalkyl; X is CR_(A)R_(B), O, NR₇ or a bond; R₇ is hydrogen, or C₁-C₄alkyl; R_(A) and R_(B) are independently selected from hydrogen and C₁-C₄alkyl, or R_(A) and R_(B), taken in combination, form a divalent C₂-C₅alkylene group; Z is CR₈ or N; when Z is N, X is a bond; R₈ is hydrogen or taken in combination with R₆ form a double bond; or B is a group of the formula:

wherein p and q are independently selected from the group consisting of 0, 1, and 2; R₉ and R₁₃ are independently selected from hydrogen and C₁-C₄alkyl; R₁₀ and R₁₄ are independently selected from hydrogen, amino, mono- and di-C₁-C₄akylamino and C₁-C₄alkyl, which alkyl is optionally substituted with hydroxy, amino or mono- and di-C₁-C₄alkylamino; R₁₁ is hydrogen, C₁-C₄alkyl, amino or mono- and di-C₁-C₄alkylamino; R₁₂ is hydrogen or C₁-C₄alkyl; or R₉ and R₁₁, taken in combination form a saturated azacycle having 4 to 7 ring atoms which is optionally substituted with 1-3 C₁-C₄alkyl groups; or R₁₁ and R₁₂, taken in combination form a saturated azacycle having 4 to 7 ring atoms which is optionally substituted with 1-3 C₁-C₄alkyl groups.
 2. A compound of claim 1, or a salt thereof, wherein A is 6 member heteroaryl having 1-3 ring nitrogen atoms, which 6 member heteroaryl is substituted by phenyl or a heteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatoms independently selected from N, O and S and substituted with 0, 1, or 2 substituents independently selected from C₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- and di-C₁-C₄alkylaminoC₁-C₄alkyl; or A is bicyclic heteroaryl having 9 to 10 ring atoms and 1, 2, or 3 ring heteroatoms independently selected from N, O or S, which heteroaryl is substituted with 0, 1, or 2 substituents independently selected from cyano, halogen, hydroxy, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy and C₁-C₄alkoxy substituted with hydroxy, C₁-C₄alkoxy, amino and mono- and di-C₁-C₄alkylamino.
 3. A compound of claim 1, or a salt thereof, wherein A is 2-hydroxy-phenyl which is substituted with 0, 1, 2, or 3 substituents independently selected from C₁-C₄alkyl, haloC₁-C₄alkyl C₁-C₄alkoxy, hydroxy, cyano, halogen, amino, mono- and di-C₁-C₄alkylamino, heteroaryl and C₁-C₄alkyl substituted with hydroxy or amino, which heteroaryl has 5 or 6 ring atoms, 1 or 2 ring heteroatoms selected from N, O and S and substituted with 0, 1, or 2 substituents independently selected from C₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino, hydroxyC₁-C₄alkyl, 4-7member heterocycleC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- and di-C₁-C₄alkylaminoC₁-C₄alkyl.
 4. A compound of claim 1, or a salt thereof, wherein A is 2-naphthyl optionally substituted at the 3 position with hydroxy and additionally substituted with 0, 1, or 2 substituents selected from hydroxy, cyano, halogen, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkoxy, wherein the alkoxy is unsubstituted or substituted with hydroxy, C₁-C₄alkoxy, amino, N(H)C(O)C₁-C₄alkyl, N(H)C(O)₂ C₁-C₄alkyl, 4 to 7 member heterocycle and mono- and di-C₁-C₄alkylamino; or
 5. A compound according to claim 1, or a salt thereof, wherein B is a group of the formula:

Wherein m, n and p are independently selected from 0 or 1; R, R₁, R₂, R₃, and R₄ are independently selected from the group consisting of hydrogen, C₁-C₄alkyl, which alkyl is optionally substituted with hydroxy, amino or mono- and di-C₁-C₄alkylamino; R₅ and R₆ are hydrogen; or R and R₃, taken in combination form a fused 5 or 6 member heterocyclic ring having 0 or 1 additional ring heteroatoms selected from N, O or S; R₁ and R₃, taken in combination form a C₁-C₃alkylene group; R₁ and R₅, taken in combination form a C₁-C₃alkylene group; R₃ and R₄, taken in combination with the carbon atom to which they attach, form a spirocyclicC₃-C₆cycloalkyl; X is CR_(A)R_(B), O, NR₇ or a bond; R_(A) and R_(B) are independently selected from hydrogen and C₁-C₄alkyl, or R_(A) and R_(B), taken in combination, form a divalent C₂-C₅alkylene group; Z is CR₈ or N; when Z is N, X is a bond; R₈ is hydrogen or taken in combination with R₆ form a double bond.
 6. A compound according to claim 1, or a salt thereof, wherein B is a group of the formula:

wherein p and q are independently selected from the group consisting of 0, 1, and 2; R₉ and R₁₃ are independently selected from hydrogen and C₁-C₄alkyl; R₁₀ and R₁₄ are independently selected from hydrogen, amino, mono- and di-C₁-C₄akylamino and C₁-C₄alkyl, which alkyl is optionally substituted with hydroxy, amino or mono- and di-C₁-C₄alkylamino; R₁₁ is hydrogen, C₁-C₄alkyl, amino or mono- and di-C₁-C₄alkylamino; R₁₂ is hydrogen or C₁-C₄alkyl; or R₉ and R₁₁, taken in combination form a saturated azacycle having 4 to 7 ring atoms which is optionally substituted with 1-3 C₁-C₄alkyl groups; or R₁₁ and R₁₂, taken in combination form a saturated azacycle having 4 to 7 ring atoms which is optionally substituted with 1-3 C₁-C₄alkyl groups.
 7. A compound according to claim 1, or a salt thereof, which compound is represented by Formula (II):

Wherein R₁₅ is hydrogen, hydroxyl, C₁-C₄alkoxy, which alkoxy is optionally substituted with hydroxy, methoxy, amino, mono- and di-methylamino or morpholine.
 8. A compound according to claim 1, or a salt thereof, which compound is represented by Formula (III):

Wherein R₁₆ is a 5 member heteroaryl having one ring nitrogen atom and 0 or 1 additional ring heteroatom selected from N, O or S, wherein the heteroaryl is optionally substituted with C₁-C₄alkyl.
 9. The compound of claim 1, wherein B is selected from the group consisting of

Wherein X is O or N(Me); and R₁₇ is hydrogen or methyl.
 10. A compound, or salt thereof, according to claim 1, wherein X is —O—.
 11. A compound, or salt thereof, according to claim 1, wherein B is:


12. The compound, or salt thereof, according to claim 8, wherein R₁₆ is:


13. A compound, or salt thereof, according to claim 1, wherein the compound is of formula (IV):

wherein X is —O— or

R′ is a 5-membered heteroaryl optionally substituted with 0, 1, or 2 groups selected from oxo, hydroxy, nitro, halogen, C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkoxy, C₃-C₇cycloalkyl, C₁-C₄alkyl-OH, trihaloC₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, —C(O)NH₂, —NH₂, —NO₂, hydroxyC1-C₄alkylamino, hydroxyC₁-C₄alkyl, 4-7member heterocycleC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- and di-C₁-C₄alkylaminoC₁-C₄alkyl.
 14. A compound or salt thereof selected from the group consisting of 6-(naphthalen-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine; 6-(benzo[b]thio-phen-2-yl)-N-methyl-N-(2,2,6,6-tetra-methylpiperidin-4-yl)pyridazin-3-amine; 2-(6-(2,2,6,6-tetramethylpiperidin-4-ylamino)-pyridazin-3-yl)phenol; 2-(6-(methyl-(2,2,6,6-tetra-methylpiperidin-4-yl)amino)pyridazin-3-yl)benzo[b]-thiophene-5-carbonitrile; 6-(quinolin-3-yl)-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine; 3-(benzo[b]-thiophen-2-yl)-6-(2,2,6,6-tetra-methylpiperidin-4-yloxy)pyridazine; 2-(6-(methyl-(2,2,6,6-tetra-methylpiperidin-4-yl)amino)-pyridazin-3-yl)phenol; 6-(6-(methyl-(2,2,6,6-tetra-methylpiperidin-4-yl)amino)-pyridazin-3-yl)naphthalen-2-ol; 6-(benzo[b]-thiophen-2-yl)-N-(2,2,6,6-tetra-methylpiperidin-4-yl)pyridazin-3-amine; 7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline; 6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline; N-methyl-6-(quinolin-7-yl)-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine; N-methyl-6-(quinolin-6-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine; 6-(isoquinolin-7-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine; 6-(isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine; 6-(imidazo[1,2-a]pyridin-6-yl-pyridazin-3-yl)-methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine; methyl-[6-(6-phenyl-pyridin-3-yl)-pyridazin-3-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine; methyl-[6-(6-pyrrol-1-yl-pyridin-3-yl)-pyridazin-3-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine; methyl-[6-(6-pyrazol-1-yl-pyridin-3-yl)-pyridazin-3-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine; methyl-(6-quinoxalin-2-yl-pyridazin-3-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine; methyl-(6-quinolin-3-yl-pyridazin-3-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine; N-methyl-6-(phthalazin-6-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine; 6-(benzo[c][1,2,5]oxa-diazol-5-yl)-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine; 6-(benzo[d]thiazol-5-yl)-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine; 6-(2-methylbenzo-[d]oxazol-6-yl)-N-(2,2,6,6-tetramethyl-piperidin-4-yl)pyridazin-3-amine; 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol; 5-chloro-2-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 3-(6-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyridazin-3-yl)naphthalen-2-ol; 5-chloro-2-(6-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyridazin-3-yl)phenol; 4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile; 3-[6-(2,2,6,6-tetramethyl-piperidin-4-yloxy)-pyridazin-3-yl]-naphthalen-2-ol; 2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-4-trifluoromethyl-phenol; 2-fluoro-6-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol; 3,5-dimethoxy-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol; 4,5-dimethoxy-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol; 5-methoxy-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]pyridazin-3-yl}-phenol; 4,5-difluoro-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol; 5-fluoro-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol; 3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile; 1-allyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol; 6-(benzo[b]thiophen-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine; N-allyl-3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzamide; 2-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; 5-(5-methyl-oxazol-2-yl)-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]pyridazin-3-yl}-phenol; 5-(4-hydroxymethyl)-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(1H-imidazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethyl-piperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(4-amino-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(4-amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(3-amino-pyrazol-1-yl)-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]pyridazin-3-yl}-phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-(2-morpholino-ethyl)-1H-pyrazol-4-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol; 5-(5-amino-1H-pyrazol-1-yl)-2-(6-(methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)amino) pyridazin-3-yl)phenol; 2-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-1-yl)phenol; 2-{6-[(2-hydroxy-ethyl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]pyridazin-3-yl}-5-pyrazol-1-yl-phenol; 2-(6-(piperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; 2-(6-(((2S,4R,6R)-2,6-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; 2-(6-((-2,6-di methyl piperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; 2-(6-((-2,6-di methyl piperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; 5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-yloxy)pyridazin-3-yl)phenol; 2-(6-((-2-methylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; (S)-5-(1H-Pyrazol-1-yl)-2-(6-(pyrrolidin-3-ylmethoxy)pyridazin-3-yl)phenol; (R)-5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-ylmethoxy)pyridazin-3-yl)phenol; 2-(6-((3-fluoropiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)-phenol; 2-[6-(1,2,2,6,6-pentamethyl-piperidin-4-yloxy)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 5-pyrazol-1-yl-2-[6-(2,2,6,6-tetramethyl-piperidin-4-yloxy)-pyridazin-3-yl]-phenol; 5-(1H-Pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol.; 2-(6-piperazin-1-yl-pyridazin-3-yl)-5-pyrazol-1-yl-phenol; 3-[6-(azetidin-3-ylamino)-pyridazin-3-yl]-naphthalen-2-ol; 2-[6-(azetidin-3-ylamino)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 2-[6-(3,5-di methyl-piperazin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 2-[6-(7-methyl-2,7-diaza-spiro[4.4]non-2-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 2-(6-[1,4]diazepan-1-yl-pyridazin-3-yl)-5-pyrazol-1-yl-phenol; 2-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridazin-3-yl}-5-pyrazol-1-yl-phenol; 2-[6-(3,6-diaza-bicyclo[3.2.1]oct-3-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 2-[6-(2,7-diaza-spiro[3.5]non-7-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 2-[6-(3-hydroxy-methyl-piperazin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 2-[6-(1,7-diaza-spiro[4.4]non-7-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 2-[6-(4-amino-4-methyl-piperidin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 2-[6-(3-dimethyl-amino-piperidin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 2-[6-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 2-[6-(3,3-di methyl-piperazin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol; 2-(6-(7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]-nonan-2-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; 3-(6-(piperazin-1-yl)pyridazin-3-yl)naphthalene-2,7-diol; 5-pyrazol-1-yl-2-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-phenol; 2-(6-piperidin-4-yl-pyridazin-3-yl)-5-pyrazol-1-yl-phenol; 3-(6-(1,2,3,6-tetra-hydropyridin-4-yl)pyridazin-3-yl)naphthalen-2-ol; 3-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol; 3-(6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol; 3-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol; 3-(6-(piperidin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol; 3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalene-2,7-diol; 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol; 3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol; [3-(7-hydroxy-6-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-yloxy)-propyl]-carbamic acid tert-butyl ester; 7-(3-amino-propoxy)-3-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-ol; N-[3-(7-hydroxy-6-{6[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-yloxy)-propyl]-acetamide; 7-(3-hydroxypropoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol; 7-(3-methoxypropoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol; 7-(2-morpholinoethoxy)-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalen-2-ol; 3-(6-(piperidin-4-ylmethyl)pyridazin-3-yl)naphthalen-2-ol; 5-(1H-pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol; 3-methoxy-2-(6-(methyl(2,2,6-trimethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol; 2-(6-((6S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2-naphthonitrile; 3-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(piperidin-1-ylmethyl)naphthalen-2-ol; 3-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(pyrrolidin-1-ylmethyl)naphthalen-2-ol; 1-bromo-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol; 1-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol; 7-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol; 7-methoxy-3-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol; 7-(3,6-dihydro-2H-pyran-4-yl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol; 3-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)naphthalen-2-ol; 7-(difluoromethyl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol; 7-((4-hydroxy-2-methylbutan-2-yl)oxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol; 7-(3-hydroxy-3-methylbutoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol; 2-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)benzene-1,3-diol; 3-methoxy-2-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol; 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenol; 4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyl)-1-methylpyridin-2(1H)-one; 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol; 3-methoxy-2-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)phenol; 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(pyridin-3-yl)phenol; 5-(1-cyclopentyl-1H-pyrazol-4-yl)-3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 3′,5-dimethoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-[1,1′-biphenyl]-3-ol; 3-(benzyloxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol; 3-ethoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol; 3-(cyclopropyl methoxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol; 2-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1H-benzo[d]imidazol-6-ol; 5-chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(1H-pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile; 2-(6-((2,2-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-4-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenol; 4-(1H-indol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 4-(cyclopent-1-en-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-3-yl)phenol; 4-(4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-2-ol; 4-(4-hydroxy-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one; 4-(4-hydroxy-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)pyridin-2-ol; 5-(1H-indazol-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 4-chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol; 4-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol; 5-fluoro-4-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-4-yl)phenol; 5-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-5-yl)phenol; 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one; 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1,4-dihydroindeno[1,2-c]pyrazol-7-ol; 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one oxime hydrochloride salt; 5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-indene-1,6-diol; 2-amino-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-8H-indeno[1,2-d]thiazol-5-ol hydrochloride salt; 9-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5,6-dihydroimidazo[5,1-a]isoquinolin-8-ol hydrochloride salt; 4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide; 4-(4-(hydroxymethyl)-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol; 6-(3-(benzyloxy)isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine; 6-(1-(benzyloxy)isoquinolin-7-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine; 3-fluoro-5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol hydrochloride salt; 4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-2(1H)-one hydrochloride salt; 4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one hydrochloride salt; 5-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one hydrochloride salt; 3-fluoro-5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol hydrochloride salt; 5-chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol hydrochloride salt; 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol hydrochloride salt; 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol hydrochloride salt; 5-(5-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(3-hydroxy-4-(6-methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-2-ol; 4-(3-hydroxy-4-(6-methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-2-ol; 5-(6-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-3-(trifluoromethyl)pyridin-2-ol; 5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one; 4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one; 5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 4-(3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)pyridin-2-ol; 5-(6-(dimethylamino)pyridin-3-yl)-2-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 4-(3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(pyrimidin-5-yl)phenol; 5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-3-ol; 1-cyclopropyl-4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)pyridin-2(1H)-one; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)phenol; 5-(cyclopent-1-en-1-yl)-2-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(3,6-dihydro-2H-pyran-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(imidazo[1,5-a]pyridin-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(imidazo[1,2-a]pyridin-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(2-methylpyridin-4-yl)phenol; 5-(1H-imidazol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 5-(imidazo[1,2-a]pyrazin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(4-methyl-1H-imidazol-2-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-imidazol-4-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-imidazol-5-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(4-nitro-1H-imidazol-2-yl)phenol; 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(2-methyl-1H-imidazol-4-yl)phenol; 5-(1,2-dimethyl-1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol; 1-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1H-pyrazole-4-carboxamide; 2-(6-((3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol; 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol; 2-(6-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol; 4-(3-hydroxy-4-(6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one; 4-(3-hydroxy-4-(6-((3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one; 2-(6-(2,7-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol; and 4-(4-(6-(2,7-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl)-3-hydroxyphenyl)-1-methylpyridin-2(1H)-one.
 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
 16. A combination comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents.
 17. A method to treat, prevent or ameliorate an SMN-deficiency-related condition, comprising administering to a subject in need thereof an effective amount of a compound or salt thereof of claim
 1. 18. The method of claim 17, wherein said SMN-deficiency-related condition is Spinal Muscular Atrophy. 